Drugs in Clinical Trials for Alzheimer's Disease - Wiley Online Library

Drugs in Clinical Trials for Alzheimer’s Disease: The Major Trends Sergey O. Bachurin, Elena V. Bovina, and Aleksey A. Ustyugov Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severny proezd 1, Chernogolovka, Moscow region, 142432, Russia Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.21434

䉲 Abstract: Alzheimer’s disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current “anti-Alzheimer’s” agents currently in clinical trials based on findings available in the Thomson Reuters «Integrity» database, on the public website www.clinicaltrials.gov, and on database of the website Alzforum.org. As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so-called “disease-modifying agents”) — these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti-Alzheimer’s) application offers a very C 2017 Wiley Periodicals, Inc. Med. Res. attractive approach to facilitate the completion of clinical trials. Rev., 37, No. 5, 1186–1225, 2017

Key words: neurodegenerative disease; Alzheimer’s disease; multitargeting compounds; disease-modifying drugs; repositioning of old drugs; clinical trial; AD treatment; amyloid-beta; Tauopathy; proteinopathy

1. INTRODUCTION Research and development of efficient therapeutic agents for the treatment of neurodegenerative diseases (NDD) is one of the most risky and challenging problems of modern medicinal chemistry. At the same time, the socioeconomic importance of the development of such medicines outweighs any possible risks and development costs. For example, in the United States alone Correspondence to: Sergey O. Bachurin, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severny proezd 1, Chernogolovka, Moscow region 142432, Russia. E-mail: [email protected]. Medicinal Research Reviews, 37, No. 5, 1186–1225, 2017 C 2017 Wiley Periodicals, Inc.

DRUGS IN CLINICAL TRIALS FOR ALZHEIMER’S DISEASE

r 1187

in 2010–2011, the economic damages from Alzheimer’s disease (AD) exceeded $215 billion.1 According to current reports, the worldwide sales of drugs for the treatment of AD by 2017 would reach $8.3 billion. A review by Cammings et al. reports that 413 clinical trials of 244 potential drugs proposed for the treatment of AD were conducted during 2002–2012, of which 124 studies entered phase I, 206 were in phase II, and 83 in phase III. Since 2007, when the Food and Drug Administration in the United States introduced a mandatory registration of clinical trials, only 54 tests reached the third phase.2 However, despite the enormous efforts and costs in search for new and effective agents for AD treatment in the past decade, there are still no new drugs on the market. In general terms, AD is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid (Aβ) and hyperphosphorylated Tau.3, 4 Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood, yet it is clear that advanced age is the main risk. There are various theories and hypotheses depicting the causal factors, all of which lead to the conclusion that AD is a multifactorial disease and hence there could not be just one curative agent to battle the progression of the pathology5, 6 (Fig. 1). Despite the most popular AD theories the amyloid hypothesis7 and the Tau theory,8 others include the following: (i) chemical factors leading to metal dysmetabolism and altering signal transduction; (ii) vascular disturbances resulting in poor blood supply to the brain; (iii) preexisting conditions such as diabetes, high blood pressure, and high cholesterol; (iv) genetic predisposition including mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes as well as allelic variation in apolipoprotein E (ApoE); (v) immune system dysfunction; (vi) mitochondrial dysfunction; (vii) disruption in the manufacture of nerve growth factors; and (viii) environmental factors and infectious agents.9–12 A small portion of AD cases are due to genetic mutations leading to an autosomal dominant inheritance pattern in three genes — APP, PSENs 1 and 2.13–16 All patients having mutations in these genes showed premature development of the disease. Thus, these genes or rather their protein products are the initial targets for drug development. Further studies uncovered APP cleavage by beta-secretase and subsequent gamma-secretase (which is comprised of PSEN) leading to formation of an Aβ product that is prone to aggregate and forms toxic oligomeric structures that interact with a number of neuronal receptors, triggering a cascade of events that are responsible for mitochondria dysfunction, Ca2+ imbalance, lipid peroxidation, DNA damage, and other factors leading to neuronal death. Genetic predisposition is not the major causal factor, and the sporadic nature of AD involves other factors that have also been linked with the development of the disease: smoking, educational level, and a low level of physical and mental activity. Despite a lack of knowledge of the complete AD molecular pathway, the pathological markers of AD are very well documented. These are neurofibrillary tangles (NFTs) formed by aggregated Tau protein and neuritic plaques comprised of Aβ. Under normal conditions, Tau protein stabilizes microtubules in the cytoskeleton of neurons.17, 18 However, in pathological conditions, Tau is abnormally hyperphosphorylated and no longer binds to microtubules, forming insoluble aggregates in the intracellular space of the neuron, disrupting the axonal transport, and inevitably resulting in neuronal death. Comparative analysis of cerebrospinal fluid (CSF) and blood biomarkers for the diagnosis of AD showed that the core CSF biomarkers of neurodegeneration, first of all T-tau and P-tau, as well as Aβ42, CSF NFL (neurofilament protein) and plasma T-tau were strongly associated with AD. Furthermore, plasma T-tau and CSF NFL had largest effect sizes when differentiating between controls and patients with AD. Other assessed biomarkers had only marginal effect sizes or did not differentiate between control and patient samples.19 NPs are present both in the extracellular and intracellular compartments, Medicinal Research Reviews DOI 10.1002/med

1188

r BACHURIN, BOVINA, AND USTYUGOV

Figure 1. A schematic illustration of interrelation of possible molecular targets used for discovery of innovative drugs for AD treatment and prevention.

and they are formed by a 39–42 amino acid fragment with a molecular weight of 4 kDa.20, 21 Small soluble oligomers and intermediate fibrils are the most toxic to nerve cells, while the final products of aggregation are relatively inert. This applies both for β-amyloid as well as for Tau protein.22, 23 In recent years, several dozens of reports were published analyzing various aspects of the pathogenesis and pharmacotherapy of AD and related dementia.24–29 To date, the most widely used anti-AD drugs in clinical practice are Donepezil (Aricept), Galantamine (Reminyl), Rivastigmine (Exelon), and Memantine (Noojerone). The first three are acetylcholinesterase (AChE) inhibitors (AChEI), whereas memantine is a low-affinity noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors (GluR). Initially, the first generation of cholinesterase inhibitors (ChEI) such as tacrine (approved since 1993) have nonselectively inhibited AChE with respect to the other enzymes of this group — butyrylcholinesterase (BuChE) — and have showed low organ specificity. Currently, these drugs are Medicinal Research Reviews DOI 10.1002/med


r 1189

for the most part phased out. One of the approaches used to improve the portability of a class of drugs, they are intended to increase the selectivity of the inhibition of AChE with respect to BuChE, which should reduce the peripheral toxicity of these compounds. This approach was implemented in the development of the second generation of ChEI, which includes Aricept (approved since 1996) and galantamine (approved since 2001), both showing a pronounced selectivity toward AChE. Another successful tactic was realized by Novartis with the development of rivastigmine (approved since 1998), which was based on a pronounced regioselectivity, providing selective inhibition of brain AChE rather than peripheral cholinesterase isoforms. All of these drugs were better tolerated compared to tacrine, and showed some efficacy at the early and moderate stages of AD. Furthermore, it was recently shown that in addition to the anticholinergic activity these drugs also affected the processing of APP protein, and thus may be potentially used for the delaying of neurodegenerative processes in AD patients.30 On the other hand, AChEI often leads to the increased levels of phosphorylated Tau that could potentially lead to a weakened therapeutic effect.31 The last drug that has been introduced on the market for the treatment of moderate-tosevere forms of AD was memantine, introduced in 2003, which binds to intrachannel site of NMDA receptor (NMDAR). Initially, it was thought that the cognitive-stimulating properties of memantine are attributed to an improved signal-to-noise ratio in glutamatergic neurotransmission due to the optimal voltage-dependent blockade of the NMDA channel site of the brain receptor.32 Recent studies suggest that the therapeutic effect of memantine could be associated also with the ability to block the β-amyloid toxic effect, realized, in particular, via interaction with brain NMDARs.33 In recent years, the strategy for AD drug discovery and development has been changed significantly.

2. CURRENT STRATEGIES OF AD DRUG DEVELOPMENT In order to identify major trends in the discovery of novel “anti-Alzheimer’s” drugs, we analyzed available data on agents that are currently at various phases of clinical trials for AD treatment. The following review summarizes findings available in the «Integrity» database (Thomson Reuters); the data posted on the Alzforum.org database, as well the public website www.clinicaltrials.gov that tracks clinical trials since 2007. On June 1, 2016, there were 34 (28%) drugs at phase I, 57 (47%) compounds were in phase I/II and II, and 30 (25%) reached phase III clinical trials on AD patients (Fig. 2). All these drugs could be subdivided into several groups according to the main targets or pathways of their action (Fig. 3). A. Anti-Beta-Amyloid Agents In the amyloid cascade, Aβ peptide is generated by the proteolytic cleavages of APP that belongs to a large family of type I membrane proteins with a large extracellular domain and a short cytoplasmic region which are derived by differential splicing of a single gene transcript located on the long arm of chromosome 21.34 The nonamyloidogenic pathways involves APP cleavage by alpha-secretase within the Aβ domain preventing the formation of potentially toxic Aβ peptides that are generated when APP is cleaved via a two-step proteolytic process involving β- and γ -secretases resulting in Aβ40 and Aβ42.35 Both types of peptide could be found in amyloid plaques, but Aβ42 has a greater propensity to aggregate-forming toxic oligomers that are further packaged into amyloid plaques36 (Fig. 4). Aβ42 is highly fibrillogenic and deposited early in individuals with AD and Down’s syndrome. Intracellular assembly occurs stepwise from the monomeric form to oligomers, protofibrils, and fibrils. The monomeric species Medicinal Research Reviews DOI 10.1002/med

1190


III

I

30 (25%)

34 (28%)

II

57 (47%) Figure 2. Distribution of clinical trials by phases (based on data available in June 2016 in the Thomson Reuters «Integrity» database, www.clinicaltrials.gov and Alzforum.org websites). The roman numerals indicate corresponding clinical trial phase, Arabic number corresponds to the actual number of compounds in trials with the corresponding percentage in brackets.

Figure 3. Distribution of drug mode of action by phases (based on data available in June 2016 in the Thomson Reuters «Integrity» database, www.clinicaltrials.gov and Alzforum.org websites). Due to multitarget action of some compounds, some might be involved in more than one group.

are not pathological; however, the nucleation-dependent fibril formation related to protein misfolding makes the Aβ toxic. Formation of Aβ is interlinked with Tau hyperphosphorylation, disruption of mitochondria function, dysregulation of calcium homeostasis, synaptic failure, and cognitive dysfunction (Fig. 1). By far the most attractive approach to AD treatment involved the development of drugs that in one way or another are affecting the stability, removal, or Medicinal Research Reviews DOI 10.1002/med


r 1191

Figure 4. A schematic representation of beta-amyloid pathway that leads to AD pathology. The cleavage of APP β-secretase and subsequently by γ -secretase results in the production of an amyloid plaque. The nonpathogenic (nonamyloidogenic pathway) is initiated by α-secretase releasing sAPPα into the intracellular space. The resulting CTF-α fragment is cleaved by γ -secretase in the intermembrane space resulting in both the AICD and p3 fragments that are both non-plaque forming elements. The pathogenic (amyloidogenic pathway) initiated by β-secretase and resulted in sAPP-β release externally. The remaining CTF-β fragment is cleaved by γ -secretase and releases Aβ38-42 amino acid amyloid monomers. The externally released Aβ fragment forms toxic oligomers and eventually packaged in amyloid plaques.

aggregation of Aβ. The initial hypothesis to deploy the immune system turned out to be successful and a growing number of vaccines as antiamyloid agents have been developed since. 1. Vaccines Among the most successful vaccine is Solanezumab (Ely Lilly)37, 38 acting on the soluble monomeric forms of the protein. Interestingly, the antibody failed in two large phase III studies, but a subset of patients who were in the early stages of the disease appeared to benefit from it. Lilly is well along in the phase III trial to test the drug on a narrower group of patients and it expects to have results by October 2016. If they are favorable, then the first disease-modifying drug for Alzheimer’s could reach patients in 2017. After the success story of solanezumab, Biogen Co. received permission to initiate phase III clinical trials following the successful completion of phase I of its vaccine — Aducanumab, which is a human monoclonal IgG1 antibody anti-Aβ derived from an AD patient and produced by the reverse translational medicine method and expressed in Chinese hamster ovary cell line (CHO) cells acting on the aggregated forms of Aβ.39 In parallel, Hoffmann-La Roche initiated trials of Gantenerumab, which is also based on immunoglobulin IgG1.40 Additionally, Grifols is conducting a trial including a combination of IGIV41 — a liquid form of pasteurized highly purified human immunoglobulin IgG with albumin in patients with mild-to-moderate forms of AD. Gammagard,42, 43 another vaccine based on IgG immunoglobulin, was tested by Baxalta; however, data on future development of this drug are not available. Unlike the successes in the aforementioned vaccines, Bapineuzumab (OOP & Johnson),44, 45 which represents a humanized monoclonal antibody acting on soluble forms of amyloid, suffered a huge blow. As a result, it was discontinued in phase III clinical trials for the treatment of mild-to-moderate AD in carriers and noncarriers of ApoE4 because the coprimary clinical endpoints were not met in clinical evaluation. It was the most serious disappointment in the field of anti-AD research in recent years. The net loss from the negative results of these tests was estimated $340 million.46 AFFiRiS developed the “affitope” technology where specific antibodies act against short fragments of antigens that do not cause autoimmune side effects. The company is currently Medicinal Research Reviews DOI 10.1002/med

1192


testing drug AD-0447, 48 acting on Aβ peptides. Previously, the same company carried out the phase II trial on a different vaccine — AD-02,49 which selectively targets Aβ-40-42 peptides but at the moment data on further development of this drug are not available. ACI-24 is an oligospecific liposome-based vaccine candidate bearing a tetra-palmitoylated amyloid beta (Abeta)1-15 peptide developed using AC Immune’s Supramolecular Technology.50 Eisai developed BAN-2401 as a novel monoclonal antibody that selectively binds, neutralizes, and eliminates soluble protofibrils, which are the toxic Aβ aggregates.51 In September 2015, United Biomedical launched UB-311, a vaccine that combines the N-terminus sequences of amyloid-beta 1–14 peptide immunogens with a foreign T-helper epitopes.52, 53 Another drug, Crenezumab, a humanized monoclonal antibody, IgG4kappa, targeting both soluble and aggregated amyloid-beta, was introduced by AC Immune and Genetech54 and initially did not pass phase II, but then subsequently was reinitiated in phase I at a higher dose (currently its on phase II). By contrast, Ponezumab (PN-1219 developed by Pfizer),55 representing a humanized monoclonal antibody IgG2kappa, did not pass phase II in AD patients, yet it is currently undergoing the phase II in patients with cerebral angiopathy. The past decade of research was devoted to effective vaccines for the treatment of AD and mild cognitive impariment (MCI) based on various forms of immunoglobulins. Normal human immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents. IgG competitively blocks Fc-gamma receptors, prevents binding and uptake of phagocytes, and reduces the number of platelets. It is widely used for the treatment of primary immunodeficiency syndromes such as X-linked agammaglobulinemia and hypogammaglobulinemia, severe combined immunodeficiency conditions, chronic lymphocytic leukemia with severe secondary hypogammaglobulinemia, and a number of other diseases. Octapharma AG is developing intravenous immunoglobulin (IVIG), also known as Octagam, in a form of liquid preparation of highly purified IgG, which is being evaluated in phase II clinical studies for the treatment of mild-to-moderate AD and in phase III clinical studies for the treatment of multiple sclerosis. It was previously shown to have an effect in AD patients.56 Although the extent and duration of the trail were insufficient to draw final conclusions, the study by 18FDG-PET-imaging showed a significant dose-dependent attenuation of the regional reduction of glucose metabolism, which is a hallmark of AD, in all patients treated with 10% octagam as compared with the placebo group. It was also noted that treatments with lower doses were more effective than with higher doses. There are nine vaccines on phase I clinical trials: five of them are agents that affect Aβ (without specifying on what type of amyloid form). These include drugs based on monoclonal antibodies SAR-228810 (Sanofi Company),57 MEDI-1814 (AstraZeneca),58 KHK-6640 (Kyowa Hakko Kirin),59 and two based on recombinant proteins Lu-AF-20513 (Lundbeck)60 and TTP4000 (Trans Tech Pharma).61 2. APP-Processing Enzyme Inhibitors In addition to vaccines, there are numerous chemical compounds that affect amyloid pathology pathway. These include several pivotal points that trigger accumulation of pathogenic Aβ. One of the most attractive approaches to inhibition of enzymes involved in APP cleavage resulted in Aβ peptide formation. These are beta- and gamma-secretases — directly related to Aβ production and to activation of alpha-secretase, which catalyzes APP cleavage, generating a nonpathogenic amyloid peptide (see Fig. 1). The majority of developing drug-candidates represent inhibitors of beta-secretase (BACE-1). In particular, MK8931 or Verubecestat62 developed by Merck & Co.; an orally administered AZD-3293 (LY-3314814)63 developed jointly by AstraZeneca and Eli Lilly; and JNJ-54861911 (Janssen Research & Development)64 are currently in phase III for treatment of mild and moderate AD. BACE-1 inhibitor E-2609 (Eisai)65 is on Medicinal Research Reviews DOI 10.1002/med


r 1193

phase II trials, and agent BI-1181181 (developed by Boehringer Inhelheim)66 is on phase I. Currently, there are two inhibitors of gamma-secretase in clinical trials: EVP-0962 (FORUM Pharm),67 which is an orally available modulator of this enzyme on phase II, and BMS-932481 (Bristol-Myers Squibb),68 which inhibits gamma-secretase on phase I clinical trials.

3. Antiaggregation of Beta-Amyloid In addition to vaccines and APP-processing enzyme inhibitors, there is another quite diverse group of compounds preventing aggregation of Aβ, hence stalling the accumulation and formation of amyloid plaques. Phase III clinical trials are currently underway for agent ALZT-OP1 developed by AZ Therapeutics69 for the prevention and treatment of early AD. It is a combination drug therapy consisting of the administration of two previously approved drugs, which have been shown to inhibit Aβ (Abeta) aggregation and neuroinflammation. GV-971, developed at Shanghai Green Valley for the oral treatment of mild-to-moderate AD,70 is a sodium oligo-mannurarate, and it is also in phase III clinical trials. It showed the ability to reduce the toxicity of Aβ peptide in vitro. Phase II clinical trials include several low-molecular-weight compounds that could be attributed to the general group of “antiamyloidogenic” drugs. A few years ago, Phenserine, which is a known inhibitor of AChE, was in phase III clinical trials for therapy for cognitive impairments associated with aging and AD, in order to identify its ability to reduce the level of precursor protein (APP) and Aβ in the plasma and CSF. Statistical analysis of the results showed no noticeable improvements in the performance of the experimental group compared to the placebo. Yet more detailed analyses showed positive effects in patients treated with the highest dose. QR Pharma is currently testing Posiphen, which is a (+)-isomer of phenserine acting as an antiamyloidogenic agent in phase II clinical trials for the treatment of MCI, AD, and Parkinson’s disease (PD). The drug has showed the ability to reduce the level of APP and Aβ in preclinical studies in rodents with the absence of significant side effects.71 Scyllo-Inositol (ELND005)72 is a small-molecule inhibitor of amyloid beta peptide aggregation in phase II/III clinical development at Transition Therapeutics for the oral treatment of Alzheimer’s type dementia. The major positive effects associated with the reduced aggregation in AD patients are still unpublished, though the results of clinical trials were ambiguous.73 Phase II clinical trials are also ongoing for the treatment of young adults with Down’s syndrome without dementia. Ro-63-8695 (GlaxoSmithKline)74, 75 is described as a reducing amyloidosis agent in the brain and it is known as a selective inhibitor of serum amyloid protein (SAP). It had been in early clinical development by Pentraxin Therapeutics for the treatment of Alzheimer’stype dementia. ALZ-801 (Alzheon)76 formerly known as BLU-8499 is a “prodrug” of the antiamyloidogenic agent tramiprosate targeting amyloid aggregation and it is currently in phase I trials. Special attention is drawn to a group of compounds that are targeting both amyloid plaque and NFTs — the dual hallmark pathologies of AD. Phase I clinical trials are initiated for SAN-61 (Diamedica Company)77 as a potential first-in-class agent that stimulates proliferation of neural stem cells acting simultaneously on amyloid plaques and neurofibrillary aggregates. Another agent with a dual action is a small molecule, Exebryl-1 (ProteoTech).78 It modulates β- and α-secretase activity causing substantial reduction of Aβ formation and accumulation in older Alzheimer’s transgenic animals’ brain. Initial studies suggest that Exebryl-1 may also have an important dual capacity by inhibiting and reducing Tau protein from forming the paired helical filaments important in NFT formation. Available structures for low-molecular-weight drugs affecting Aβ processing are summarized in Figure 5. Medicinal Research Reviews DOI 10.1002/med

1194


Figure 5.

Available structures for low-molecular-weight drugs affecting beta-amyloid processing.

B. Drugs Affecting Tau Aggregation It is well accepted nowadays that NFTs, one of the major hallmarks of AD, are composed of aggregated hyperphosphorylated Tau protein. Normally, the microtubule-associated protein Tau appears to be critical to neuronal activity as it facilitates microtubule stabilization within cells. However, in the disease states Tau is highly phosphorylated by different kinases, reducing its binding to microtubules and sequestering of hyperphosphorylated Tau into NFT. The loss of Tau function leads to microtubule instability and reduced axonal transport as well as emerged toxic effect from aggregated hyperphosphorylated Tau contributes to neuropathology79 (Fig. 6). As with the antiamyloid treatments, there are several vaccines that affect Tau aggregates. One of them is RG-7345 (Genetech, Hoffmann-La Roche) represents a passive Tau-based immunotherapy80 and currently is in phase I clinical trails. Another vaccine AADvac-1, developed by Axon Neuroscience,81 passed phase I trials in patients with mild-to-moderate AD and an 18-month follow-up phase I trial. Axon is currently recruiting patients for phase II trials. ACI-35 (ACImmune)82, 83 has passed phase I trials for mild-to-moderate AD. BMS-986168, an anti-microtubule-associated protein Tau, is in the early clinical trials at Bristol-Myers Squibb for the treatment of tauopathies and for the treatment of progressive supranuclear palsy.84 Great expectations in recent years are focused around a well-known disinfectant and due — Methylene blue (MB). Though the ability to block Tau aggregation by MB and its analogs was shown 20 years ago,85 recent findings for its use as an anti-Alzheimer’s agent are increased sharply mainly due to numerous failures in developing antiamyloid drugs. TauRx, an MB agent, has successfully completed phase II (TRx-0014)86, 87 in AD patients and moved onto Medicinal Research Reviews DOI 10.1002/med

Sanofi Company Suven Life Sciences Astellas Pharma

Cortice Biosciences Trans Tech Pharma

ACI-35 ALZ-801 ARC-031 ASP-3662 AUS-131 AVN-322 Basmisanil (RG-1662) BI-1181181 Bisnorcymserine BMS-932481 BMS-986168 BPN14770 Copaxone Exebryl-1 FGL-2 GC-021109 GSK-2647544 Huperzine A, Cerebra KHK-6640 Lu-AF-20513 MEDI-1814 Memogain NsG-0202 PQ-912 RG-7345 RP-5063 SAN-61

SAR-228810 SUVN-G3031 Telmisartan

TPI-287 TTP-4000

Company

GNT Pharma AC Immune’s Supramolecular Technology ACImmune Alzheon Archer Pharmaceuticals Astellas Pharma Ausio Pharmaceuticals Avineuro Roche Boehringer Inhelheim QR Pharma Bristol-Myers Squibb Bristol-Myers Squibb Tetra Discovery Partners Cedar-Sinai Medical Center ProteoTech Enkam GliaCure GSK NutriHerb Kyowa Hakko Kirin Lundbeck AstraZeneca Neurodyn Life Sciences NsGene Probiodrug AG Genetech, Hoffmann-La Roche Reviva Pharma Diamedica Company

AAD-2004 ACI-24

Name

Table I. Agents in Phase I Clinical Trials for AD Treatments.

Tau aggregation Preventing aggregation of beta-amyloid Calcium channel blocker, antioxidant Inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 Nonhormonal selective estrogen receptor beta (ER beta) agonist 5-HT6 receptor antagonist GABA(A) receptor agonist BACE-1 inhibitor Selective inhibitor of butyrylcholinesterase (BuChE) BACE-1 inhibitor Tau aggregation Phosphodiesterase inhibitor Immunomodulator Modulator of β- and α-secretase activity Stimulates the secretion of nerve growth factor Inducer of phagocytosis Inhibitor of phospholipase A2 NMDAR antagonist, signal transduction modulator, AChEI Anti-beta-amyloid Anti-beta-amyloid Anti-beta-amyloid Nonselective inhibitor of butyryl- and acetylcholinesterases Stimulates secretion of nerve growth factor Glutaminyl cyclase inhibitor Tau aggregation Multitarget Stimulates proliferation of neural stem cells acting simultaneously on amyloid plaques and neurofibrillary aggregates Anti-beta-amyloid H3R antagonist PPARalpha agonist, signal transduction modulator, PPARgamma modulator Tau aggregation Recombinant proteins affecting beta-amyloid

Cytokines inhibitor Anti-beta-amyloid

Mechanism of action or target

90 61

57 114 172, 173

82, 83 76 111 135 115 95 118 66 130, 131 68 84 140 153 78 150 160 138 203 59 60 58 132 152 144 80 96 77

159 50

References


r 1195

Medicinal Research Reviews DOI 10.1002/med


Levetiracetam Liraglutide

Dexpramipexole E-2609 Etanercept (Enbrel) EVP-0962 Exenatide Isotretinoin Ladostigil

AgeneBio Imperial College

Pfizer Avineuro Avineuro Targacept Eisai Burke Medical Research Institute Eisai Boehringer Ingelheim Alzheon Blanchette Rockefeller Neurosciences Institute NOW Foods Chang Gung Memorial Hospital Allon Therapeutics Inc., Paladin Labs Inc. Biogen Eisai Co Amgen, Inc., Pfizer FORUM Pharm NIH Hexal AG Avraham

Atorvastatin (Lipitor) AVN-101 AVN-397 AZD-3480 (Isproniciline) BAN-2401 Benfotiamine Bexarotene BI-409306 BLU-8499 Bryostatin 1

Curcumin DAOI-B (sodium benzoate) Davunetide (AL-108)

Axon Neuroscience AFFiRiS AFFiRiS Anavex Life Science

Company

AADvac-1 AD-02 AD-04 AN2/AVex-73 (Anavex-2-73)

Name

Table II. Agents in Phase II Clinical Trials for AD Treatments.

Tau aggregation Anti-beta-amyloid Anti-beta-amyloid Blocks sodium channels and acts as agonist of sigma-1 receptors and M1 muscarinic receptors, and AChE inhibitor Lowers cholesterol levels Not disclosed Not disclosed Agonist of alpha-4-beta-2-nAChR Anti-beta-amyloid Neuroprotector Anti-beta-amyloid Phosphodiesterase inhibitor Antiamyloidogenic agent Activator of protein kinase C (PKC) isozymes (delta and epsilon) Antioxidant Inhibits D-amino acid oxidases Glial cell mediator of vasoactive intestinal peptide (VIP) induced neuroprotection Dopamine receptor agonist BACE-1 inhibitor Inflammation BACE-1 inhibitor Agonists of human glucagon-like peptide-1 (amino acids 7–37) Retinoid receptors Inhibitor of acetylcholinesterase and monoamine oxidase A and B N-type calcium channel (Ca(v) 2.2) blocker Agonists of human glucagon-like peptide-1 (amino acids 7–37)


Continued

120, 121 191

118 65 162 67 192 179 133

163 105 146, 147

183, 184 199 198 100 51 175 176, 177 139 76 141

81 49 47, 48 117

References

1196


GlaxoSmithKline

Regenera Pharma Servier

RespireRx Pharmaceuticals Perrigo NIA Suven Life Sciences Toyama, FUJIFILM Osaka City University TauRx Therapeutics United Biomedical Actinogen EIP Pharma Actinogen

RPh-201 S-38093

S-47445 (CX-1632) Sargramostim (Leukine) Simvastatin SUVN-502 T-817MA Tamibarotene TRx-0014 UB-311 UE-2343 VX-745 Xanamen

Twinlab Teva GlaxoSmithKline Rockefeller University

Quercetin Rasagiline Rilapladib (SB-659032) Riluzole

Ro-63-8695

Lupin Lundbeck TauRx Therapeutics Merck & Co. Metabolic Solutions AbbVie Octapharma AG Orion Kowa Pfizer QR Pharma Probiodrug AG Pharnext

Company

LND-101001 Lu-AF-20513 Methylene Blue MK-7622 MSDC-0160 Nelonicline (ABT-126) Octagam (immunoglobulin IVIG) ORM-12741 Pitavastatin Ponezumab (PN-1219) Posiphen PQ-912 PXT-864

Name

Table II. Continued

Not disclosed Antioxidant Tau aggregation Not disclosed Antidiabetic Nicotinic alpha-7-nAChR agonist Anti-beta-amyloid Alpha 2C-adrenoceptor antagonist Statin Anti-beta-amyloid Antiamyloidogenic agent Inhibitor of glutaminekinase Multitarget: NMDAR and GABA-B antagonist, modulator of metabotropic glutamate receptors Antioxidant Monoamine oxidase type B (MAO-B) inhibitor Inhibitor of phospholipase A2 Multitarget: group of targets in the glutamatergic system and different types of ion channels Anti-human serum amyloid P (Anti-SAP), antiamyloidogenic agents Not disclosed Ionic channel modulator, antagonist of H3-histamine receptors (H3R) Ionotropic glutamate receptor Granulocyte-macrophage-stimulating agent Statin 5-HT6 receptor antagonist Neurotrophic agent Retinoic acid receptor (RAR) alpha agonist Tau aggregation Anti-beta-amyloid Inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 MAPK p38 Inhibitor Inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1


106, 107 154, 155 185, 186 93 145 178 86, 87 52, 53 134 142, 143 134

200 113

74, 75

163 136 137 122–124

195 161 85 196, 197 193 99 56 116 183 55 71 144 104

References


r 1197


Accera Accera Biogen Co. AZ Therapeutics Avanir Pharmaceuticals AstraZeneca, Eli Lilly OOP & Johnson AC Immune and Genetech Bayer Taiyo International Baxalta Hoffmann-La Roche Shanghai Green Valley NIH VitroMed Novo Nordisk GlaxoSmithKline Janssen Lundbeck AB Science

Durect, Curaxis Pharmaceutical Merck&Co Astellas Pharma Takeda Solgar, Country Life, MRM Transition Therapeutics SK Chemicals Ely Lilly Neurochem Janssen, Pfizer, TauRx Therapeutics

Crenezumab Encenicline hydrochloride

Epigallocatechin gallate Gammagard Gantenerumab GV-971 Humulin RU-100 HX-106 Insulin detemir (Levemir/Levemir300) Intepirdine (SB-742457) JNJ-54861911 Lu-AE-58054 Masitinib mesylate

Memryte

MK8931 (Verubecestat) Nilvadipine (ARC-029) Pioglitazone Resveratrol

Scyllo-Inositol (ELND005) SK-PC-B70M Solanezumab Tramiprosate TRx-00237

Company

AC-1202 AC-1204 Aducanumab ALZT-OP1 AVP-786 (CTP-786) AZD-3293 (LY-3314814) Bapineuzumab

Name

Table III. Agents in Phase III Clinical Trials for AD Treatments.

Not disclosed Stimulation of metabolic processes Anti-beta-amyloid Prevents aggregation of beta-amyloid NMDAR antagonist Inhibitors of beta-secretase (BACE-1) Humanized monoclonal antibody acting on soluble forms of amyloid Anti-beta-amyloid Acetylcholine (nicotinic) receptors ligand, nicotinic alpha-7-nAChR agonist Amyloid-related, antioxidant Anti-beta-amyloid Anti-beta-amyloid Inhibitor beta-amyloid aggregation and neuroinflammation Amyloid-related Antioxidant Not disclosed 5-HT6 receptor antagonist BACE inhibitor Serotonin receptors (5-hydrotryptamine) Inhibitor of c-KIT receptor, growth factor receptor (PDGFR), fibroblast growth factor receptor-3 (FGFR-3) tyrosine kinases Durin-leuprolide acetate and GnRH (LHRH) receptor agonist BACE-1 inhibitor Calcium channel blocker, antioxidant Inflammation Multitarget: antioxidant, MAO-A, beta-secretase, xanthine oxidase, NF-kappaB Inhibitor of amyloid beta peptide aggregation Antioxidant Anti-beta-amyloid Anti-amyloid Amyloid-related, Tau aggregation


Medicinal Research Reviews DOI 10.1002/med 72 165 37, 38 76 88

62 110 194 169, 170

108

164 42, 43 40 70 188, 189 163 190 93 64 92 109

54 98

168 174 39 69 103 63 44, 45

References

1198



r 1199

Figure 6. A schematic representation of Tau deregulation resulting in AD pathology. Under normal conditions, Tau stabilizes microtubules within neurons. Microtubules are essential for normal axonal transport. In AD and other tauopathies kinases hyperphosphorylate Tau compromising its normal function and reducing the binding of Tau to microtubules with subsequent sequestering of hyperphosphorylated Tau into neurofibrillary tangles (NFTs). The reduction of available of Tau leads to microtubule instability and reduces cellular transport further attributing to neuropathology.

Figure 7.

Available structures for drugs affecting Tau aggregation.

phase III in patients with cognitive impairment (Stanley Medical Research Institute). Data are also available for phase III trials in AD patients for TRx-00237, which is a leuco-form of MB.88 In addition, it shows signs of inhibitory properties for monoamine oxidase, nitric oxide production and as blocker of Tau aggregation. This agent is also in phase III clinical trials for the oral treatment of patients with Pick’s dementia. A quite detailed review on recent clinical trial results with MB was published recently.89 Another agent — TPI-287, a taxane derivative that demonstrates the ability to stabilize microtubular structures — is currently in phase I clinical studies for the treatment of mild-tomoderate AD and some other disorders related to disruption of intracell transport processes.90 Available structures for drugs affecting Tau aggregation are presented in Figure 7. Medicinal Research Reviews DOI 10.1002/med

1200


Figure 8.

Available structures for drugs affecting CNS receptors.

C. Drugs Affecting CNS Receptors A large group of compounds has been developed as potential anti-Alzheimer’s agents, targeting different types of neuronal receptors involved in neuronal plasticity and signal transduction. Quite often, these types of compounds are regarded as “signal modulator” drugs affecting the level of synaptic transmission. Available structures for drugs affecting central nervous system (CNS) receptors and ion channel modulators are shown in Figure 8. 1. Serotonin Receptors Ligands Serotonin (5-hydrotryptamine, 5-HT) is critically involved in regulating multiple physiological functions acting via a heterogenic receptor family that includes G-protein-coupled receptors Medicinal Research Reviews DOI 10.1002/med


r 1201

and ligand-gated ion channels. Although serotonergic neurons comprise a widely distributed and complex network that targets nearly every brain structure, the serotonin-mediated signaling is under strict temporal and spatial control. Imbalance in serotonergic signaling is implicated in many pathophysiological conditions including schizophrenia, AD, depression, and anxiety disorders. Among different groups of 5-HT receptors, most significant attention in relation to the discovery of potential anti-Alzheimer’s agent is given currently on the 6-th and 4-th serotonin receptor subtypes related to memory consolidation cognition processes.91 Among the most developed agents is Lu-AE-58054 (Lundbeck), which represents a selective 5-hydroxytryptamine receptor 6 (5-HT6R) antagonist and currently is in phase III clinical trials for the treatment moderate Alzheimer’s-type dementia as an add-on treatment to donepezil.92 Intepirdine (SB-74245793 ) is also a 5-HT6R antagonist that is in phase III clinical trials at Axovant Sciences for the treatment of patients with mild-to-moderate AD and in phase II clinical trials for the treatment of patients with dementia with Lewy bodies. The product had previously been undergoing clinical evaluation at GlaxoSmithKline for the treatment of Alzheimer’s-type dementia; however, no recent developments have been reported. SUVN-502 (Suven Life Sci.)94 is a potent, selective, brain penetrant and an orally active 5-HT6R antagonist, which is currently undergoing phase II clinical trials at Suven Life Science for the symptomatic treatment of Alzheimer’s dementia. A product structurally close to intepirdine, AVN-322 is developed by Avineuro95 and currently in phase I trials. RP-5063 (Reviva Pharma)96 is an orally active compound with a pronounced multitarget action in phase I clinical studies for the treatment of bipolar disorders, depression, Alzheimer’s and Parkinson’s psychosis, and attention deficit hyperactivity disorder. In addition to the inhibition of 5-HT6 and 5-HT7 receptors, it shows the partial agonist activity to dopamine D2, D3, and D4 receptors. 2. Acetylcholine (Nicotinic) Receptors Ligands The nicotinic acetylcholine (ACh) receptor families (nAChR) and the muscarinic ACh receptor family (mAChR) are the target of ACh in the brain. Both families of receptors are affected in AD. Recently, it was also demonstrated that Aβ interacts with nAChRs. In particular, it was shown that expression and function of nAChRs in AD is regulated by direct interactions with Aβ. Compounds designed to target these interactions may thus provide a new avenue for drug development to ameliorate cognitive symptoms in AD.97, 98 Encenicline hydrochloride is an orally available nicotinic alpha-7-nAChR agonist originated in Bayer and in-licensed to FORUM Pharmaceuticals. It is in phase III clinical trials for the treatment of cognitive deficits associated with AD and schizophrenia. The compound is also in phase II clinical studies for the treatment of nicotine dependence. In September 2015, the global program conducted by FORUM was put on clinical hold by the FDA due to serious gastrointestinal safety events reported in AD studies. In November 2015, partial clinical hold was lifted for the treatment of cognitive impairment in patients with schizophrenia. Two additional agonists of nAChR have been in phase II clinical trials. These include alpha-7-nAChR agonist Nelonicline (ABT-126 by AbbVie)99 that was proposed for the treatment of cognitive deficits in adults with schizophrenia and for the treatment of mild-to-moderate AD, and an agonist of alpha-4-beta-2-nAChR, AZD-3480 (Isproniciline),100 developed by Targacept. However, recent progress reports are not available at present. 3. Glutamate Receptors Ligands GluRs play a pivotal role in the synaptic transmission and synaptic plasticity thought to underlie learning and memory. The role of these receptors provided grounds for developing one of the first strategies in AD drug discovery among different ligands of GluR.101 Earlier, it was mentioned that one of the few medicines currently used for AD treatment is an antagonist of ion Medicinal Research Reviews DOI 10.1002/med

1202


tropic GluRs subtype-NMDAR — Memantine. This subtype of GluR still looks very attractive and a large number of companies continue in focused search of optimal ligands for NMDAR. However, only one of the direct analogs of Memantine is now in the preclinical trials — Nitromemantine, which is a derivative developed by S. Lipton.102 Another antagonist on NMDAR is AVP-786 (CTP-786), which is a drug product containing a deuterated form of dextromethorphan and quinidine sulfate and is in phase III clinical trials at Avanir for the treatment of agitation in patients with AD. It is also being tested in patients with depression and neurotic pain.103 It has a multitargeted mechanism of action and it involves a blockade of P-glycoproteins as well as activation of Sigma-1 in the brain. PXT864 (Pharnext),104 a fixed-dose combination of baclofen and acamprosate, has a pronounced multitarget agent acting as the NMDAR antagonist, an agonist of GABA-B (where GABA is gamma-aminobutyric acid) receptor, and a modulator of metabotropic GluRs. It is in phase II clinical trials. Alternative approaches connected with the activation of NMDAR were explored by researchers from Chang Gung Memorial Hospital. They proposed a compound DAOI-B that seems to be a sodium benzoate derivative inhibiting D-amino acid oxidases responsible for degrading D-serine and D-alanine, thereby raising levels of the D-amino acids that in turn act as ligands of coagonist site of NMDAR.105 The investigators hypothesized that DAOI-B may yield better efficacy than a placebo for cognitive function in patients with mild cognitive impairment or mild AD. However, though the phase II trials were completed in 2013, and data are still not available. The other ionotropic GluR subtype, the so-called α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor (AMPAR) plays a key role in memory consolidation106 and is a target for S-47445 (formerly known as CX-1632).107 This is a positive modulator of AMPAR that is in phase II clinical studies at Servier for the treatment of Alzheimer’s dementia. The product was discovered jointly by Servier and Cortex Pharma (current RespireRx Pharmaceuticals) using Ampakine technology.

4. Ligands of Other Receptors and Ionic Channels in Clinical Trials Phase III clinical trials are currently ongoing for the treatment of Alzheimer’s-type dementia108 with Memryte, which is Durin-leuprolide acetate and a GnRH (LHRH) receptor agonist. The Durin biodegradable implant technology that is used as a long-term platform for parenteral delivery of leuprolide acetate for extended release was developed by Durect in collaboration with Curaxis Pharmaceutical. The results of these trials are not published yet. Masitinib mesylate is also in phase III clinical trials conducted by AB Science for the oral treatment for a number of disorders including AD, multiple sclerosis, multiple myeloma, melanoma, and metastatic colorectal cancer. Masitinib mesylate is a selective inhibitor of receptor tyrosine kinase cKIT (c-KIT receptor), platelet-derived growth factor receptor, and fibroblast growth factor receptor-3 (FGFR-3) tyrosine kinases.109 Phase III clinical studies for Nilvadipine (ARC-029)110 are under way at the Roskamp Institute and the Trinity College Institute of Neuroscience for the treatment of Alzheimer’stype dementia. Nilvadapine is a dihydropyridine calcium channel blocker that was launched in 1989 by Astellas Pharma (formerly Fujisawa) for the oral treatment of hypertension. The drug antagonizes both L- and T-type calcium ion channels and exerts an antioxidant effect. ARC031111 from Archer Pharmaceuticals, a follow-up drug to ARC-029, works in the same way as ARC-029, but with an advantage that it does not have antihypertensive effects in comparable doses. About 20 different receptor ligands and ionic channel modulators are currently undergoing the phase II clinical trials in AD research. Two potential drugs represent the specific antagonist Medicinal Research Reviews DOI 10.1002/med


r 1203

of H3-histamine receptors (H3R), which are expressed mainly in the CNS; and consequently, it is an attractive pharmacological target in particular for AD and MCI.112 S-38093 (Servier)113 had been in phase II clinical development at Servier for the treatment of Alzheimer’s-type dementia; however, no recent developments have been reported. Another H3R antagonist is SUVN-G3031, which is in phase I at Suven Life Sciences for the treatment of cognitive disorders associated with AD patients.114 Among other neuronal receptor ligands, the following compounds should be mentioned: AUS-131 is a nonhormonal selective estrogen receptor beta agonist, which is aimed at improving the functional activity of mitochondria of the brain.115 ORM-12741 (Orion)116 is the antagonist alpha 2C-adrenoceptor. AN2/AVex-73 (Anavex-2-73 by Anavex Life Science)117 blocks sodium channels and acts as agonist of Sigma-1 receptors and M1 muscarinic receptors as well as an AChEI and it is in clinical trials in combination with donepezil. In September 2015, Dexpramipexole (Biogen)118 phase II was announced as completed and it was proposed earlier for the treatment of amyotrophic lateral sclerosis. The drug is a stereoisomer of the dopamine receptor agonist Pramipexole119 and close analog of the medication, riluzole. Basmisanil (RG1662) is a GABA(A) receptor agonist that is being developed at Roche to improve cognitive behavior for the treatment of AD type dementia. Levetiracetam, developed by AgeneBio, an N-type calcium channel (Ca(v) 2.2) blocker, was originally launched as adjunctive therapy in the oral treatment of partial-onset seizures with or without secondary generalization in adults with epilepsy, and it is now in phase II for AD patients with mild cognitive impairments.120, 121 Riluzole (Rockefeller University),122, 123 which is currently used for treatment of amyotrophic lateral sclerosis, has also launched in phase II clinical trials for AD patients. It has a multitarget mechanism of action that includes a group of targets in the glutamatergic system as well as different types of ion channels.124

D. Inhibitors of Enzymes Involved in Neuronal Signal Transduction The strategy of enzyme modulation is based on improvement or restoration of signal transduction and targets specific enzymes that are found in the AD research pipeline. Available structures for inhibitors of enzymes affecting neuronal signal transduction are shown in Figure 9.

1. Cholinesterase Inhibitors Historically, ChEI are the first and the most developed group of drugs proposed for AD treatment. According to the classical conception of the impact of AChEI on neurotransmission, the main effect of ChEI is thought to be associated with the increase of both the duration of action and concentration of the ACh neurotransmitter in the synaptic cleft, resulting in a potentiation of the activation of cholinergic receptors that are decreased in AD-type pathology.125, 126 However, the magnitude of the ChEI effect depends on the integrity of presynaptic neurons. Apparently, it will be reduced at late stages of the disease when a significant decrease in the number of terminals of cholinergic neurons is observed.127 Currently studies of ChEI are still continuing though at a lower pace. The evident peculiarities in the modern strategy for antiChEi involve a shift of attention to a much more focused search for selective inhibitors of BuChE127, 128 and specific blockers of peripheral sites of AChE assumed to be involved in the anti-Aβ action.30, 129 Currently, there is particular interest in a specific inhibitor of BuChE — Bisnorcymserine (QR Pharma)130, 131 — and a nonselective inhibitor of BuChE and AChEs — Memogain (GLN-1062 by Neurodyn Life Sci.),132 which is a derivative of a well-known AD drug — Galantamine. Both compounds are in phase I clinical trials. Medicinal Research Reviews DOI 10.1002/med

1204


Figure 9.

Available structures for inhibitors of enzymes involved in neuronal signal transduction.

A vivid example of a focused design of a multitarget agent acting on two key enzymes responsible for the neurotransmitter metabolism is implemented in Ladostigil (Avraham). It acts as an inhibitor of AChE as well as monoamine oxidase A and B. It showed promising results in phase II clinical trials but failed in phase III and currently moved on phase II trials in patients with MCI.133 Medicinal Research Reviews DOI 10.1002/med


r 1205

2. Inhibitors of 11-Beta-Hydroxysteroid Dehydrogenase Type 1 Two agents with this mechanism of action are currently in clinical trials: UE-2343 is in phase II trials conducted by Actinogen134 and ASP-3662 is in development at Astellas Pharma in phase I clinical trials for the treatment of Alzheimer’s-type dementia.135 The product is also being studied in phase II clinical trials for the treatment of painful diabetic peripheral neuropathy. 3. Monoamine Oxidase Inhibitors Rasagiline is a selective and potent, irreversible monoamine oxidase type B (MAO-B) inhibitor developed by Teva and it is based on research originating from the Technion, Israel Institute of Technology. Rasagiline had been in phase II clinical trials at Teva and Eisai for the treatment of Alzheimer’s-type dementia and in phase III clinical studies at Teva for the oral treatment of progressive supranuclear palsy as well as in phase II trials at Teva for the treatment of multiple system atrophy of the Parkinsonian subtype (MSA-P); however, no recent development has been reported for these studies. Currently, it is in phase II clinical trials by Teva as a monotherapy in patients with early PD and as an adjuvant treatment in moderate-to-advanced PD.136 4. Phospholipase A2 The inhibition of phospholipase A2 is reported as the main mechanism of action for Rilapladib (SB-659032 developed by GlaxoSmithKline).137 The clinical research in AD patients was completed in 2015, but the results are not yet available. Inhibition of this enzyme is also mentioned as the main mechanism of action for GSK-2647544, which is in phase I clinical trials initiated by GSK.138 However, no recent developments have been reported for this compound. 5. Phosphodiesterase (PDE) Inhibitors BI-409306, developed by Boehringer Ingelheim,139 targets PDE-9A and is currently in phase II clinical trials. At the end of 2015, Tetra Discovery Partners began phase I of a low-molecularweight agent BPN14770 as a novel heteroaryl derivative, which is a negative allosteric modulator of another enzyme from this class: PDE-4D.140 6. Kinase and Cyclase Inhibitors Bryostatin 1 (Blanchette Rockefeller Neurosciences Institute)141 is a potent activator of protein kinase C isozymes (delta and epsilon) and it is currently in phase II trials for the treatment of mild-to-moderate AD patients. Phase II clinical trials are also initiated for VX-745,142, 143 which acts as an MAPK p38 inhibitor (mitogen-activated protein kinase p38) — an enzyme involved in inflammatory processes in glial cells. PQ-912 is a small-molecule-weight glutaminyl cyclase inhibitor in phase I at Probiodrug AG.144 E. Other Drugs Including Antioxidants and Compounds with Undisclosed Targets or Mechanisms of Action 1. Neurotrophic Drugs Including Stem Cell Agents There are several drugs that exhibit neurotrophic effects. For example, T-817MA is a neurotrophic agent in phase II trials at Toyama and FUJIFILM145 for the oral treatment of Alzheimer’s-type dementia. The drug stimulates neurite growth and shows a neuroprotective effect by reducing oxidative stress. A short oligopeptide, Davunetide (AL-108),146, 147 containing eight amino acids residues is the smallest active element of activity-dependent neuroprotective protein, a glial cell mediator of vasoactive-intestinal-peptide-induced neuroprotection. Preclinical experiments show that it has potent neuroprotective, memory–enhancing, and neurotrophic properties. The clinical developments at Paladin had been carried out for the treatment of Medicinal Research Reviews DOI 10.1002/med

1206


MCI associated with postcardiac artery bypass graft and for the treatment of Alzheimer’s-type dementia as well as some other disorders; however, no recent developments have been reported for this compound. Medipost is conducting phase I/II clinical trials for Neurostem-AD,148, 149 which is based on mesenchymal stem cells. The product has passed phase I and moved on to phase II; however, data are not available. Several drugs in the early stages of clinical trials act as neurotrophic factors, of which two are shown as high-molecular-weight stimulants of fibroblast growth factor (FGL-2,150 FGL-lop peptide151 ; Enkam company) and another that stimulates the secretion of nerve growth factor (NsG-0202 by NsGene).152 A new study has begun testing the macromolecular drug Copaxone (Glatiramer acetate, Cedar-Sinai Medical Center)153 that belongs to the class of immunomodulators and was previously used in treatments of multiple sclerosis. Phase II has also started for Sargramostim (Leukine), which was developed by the University of Colorado for the treatment of neuropathy and prostate cancer154, 155 and which acts as a granulocyte-macrophage-stimulating agent.

2. Antiinflammatory Agents and Antioxidants The immune system is an important mediator in the pathogenesis of AD.156, 157 Immune system modulators such as nonsteroidal antiinflammatory drugs (NSAIDs) garnered initial enthusiasm from preclinical and epidemiologic studies as agents to reduce the risk of AD. While a longterm use of NSAIDs is associated with a reduced incidence of AD in epidemiologic studies, randomized controlled trials have not replicated these findings. However, new attempts at discovering more efficient anti-Alzheimer’s agents among antiinflammatory agents are still ongoing.158 In particular, GNT Pharma is developing AAD-2004159 as an inhibitor of the formation of cytokines is in phase I clinical trials as well as the compound GC-021109 by GliaCure,160 which acts as an inducer of phagocytosis. One of the best-known neuroprotective strategies for AD is antioxidant therapy, based on numerous findings that neurodegeneration processes in the CNS are often initiated or enhanced by oxidative stress, that is, an unfavorable ratio of oxidants to antioxidants.161 Several drugs currently in clinical trials are reported as antioxidants with a multitargeted mechanism of action. These are dietary supplements: Lu-AF-2053 (Lundbeck),60 Etanercept (Life Extension Found),162 Curcumin, Quercetin, fish oil, and several other ingredients, as well as HX-106 (VitroMed), which is a herbal extract.163 In August 2015, Charite University (Berlin) completed phase III for the herbal drug Epigallocatechin gallate.164 The drug is a component of Japanese green tea extract. The results have not yet been published but epigallactine gallate is likely to have a multitarget mechanism of action similar to most herbal preparations with a strong antioxidant component. Yet another herbal drug, SK-PC-B70M,165 is composed of an oleanolic-glycoside saponin-enriched fraction from traditional Korean herbal medicine Pulsatillakoreana. SK Chemicals originally developed this compound that is now in phase III clinical trials for the treatment of Alzheimer’s-type dementia. The results are not yet published. A number of drugs are currently already available as dietary supplements registered for improving the condition of AD patients and those with other cognitive pathologies. Gingko biloba extract is a phytoestrogen that is registered with Ipsen and Schwabe in 1992 as a dietary supplement that improves the cognitive function of patients with senile and peripheral vascular dementia.166 INM-176 (Alzhima 176) by SciGenic, another herbal medicine that is based on ferruginosa acid complexes and is used in some food additives, was registered as a food supplement in 2003. It has an analgesic effect and is indicated to improve the condition of AD patients by improving blood circulation as well as reducing psychiatric symptoms.167 AC-1202 was registered in 2009 as the first food supplement to improve metabolic processes in mild-to-moderate AD patients. The drug improves energy metabolism and homeostasis Medicinal Research Reviews DOI 10.1002/med


r 1207

of lipids in the brain impaired by AD and other forms of dementia.168 Resveratrol,169, 170 a typical multitargeted medicine and antioxidant, targets MAO-A, beta-secretase, xanthine oxidase, NF-kappaB, and several others enzymes. The drug has passed phase II for AD patients but it was withdrawn from phase III, and it is currently used in combination with other dietary supplements in clinical trials in patients with MCI. A widely used herbal medicine, Curcumin,171 has repeatedly been investigated in clinical trials in AD patients; however, there were no significant positive results reported so far. In 2015, the tests continued in patients with mild cognitive impairment (University of California Los Angeles, USA). The mechanism of action is not specified and the structures are not disclosed for nine drugs that are in phase I. 3. Other Agents in Clinical Trials There is an array of drugs that act on targets in the nervous system other than the primary causal factors of AD. These are most commonly used either for treatments of other diseases, not necessarily those related to dementia, or else used as dietary supplements, showing their safety in prolonged treatments. For example, Telmisartan,172, 173 currently in phase I clinical trials for the treatment of AD patients, was originally launched more than 15 years ago for the oral treatment of hypertension. Accera has announced but has not started phase II/III for Axona (AC-1204),174 which is a first-in-class drug launched as a medical food for the clinical dietary management of the metabolic processes associated with mild-to-moderate AD. The drug addresses the energy deficit observed in the brain of AD patients. Studies are ongoing for Enbrel (Neurokine),162 a recombinant fusion protein comprised of the soluble human p75 tumor necrosis factor (TNF) receptor linked to the Fc portion of human IgG1 1-235-TNF receptor (human) fusion protein with 236-467-IgG1 (human gamma1-chain Fc fragment) dimmer. Originally, it was used as an antiinflammatory agent for the treatment of rheumatoid arthritis. Clinical trials are also ongoing for the analog of vitamin B1 — Benfotiamine (Burke Medical Research Institute)175 — that is used as a prodrug as a broad-spectrum neuroprotector against neuropathies, neuralgia pathologies, and impaired coronary circulation. In recent years, an oncolytic, Bexarotene, which was previously used to treat certain forms of lymphoma,176, 177 has attracted a lot of attention. Preclinical studies in animals have shown that it causes abrupt yet reversible reduction of amyloid plaques improving cognitive functions. Thus, Cleveland Clinic Foundation initiated clinical trials for this promising drug as a treatment for AD. At this moment, bexarotene is in phase II but full data are not yet available. Other oncolytics that are structurally similar to bexarotene are being researched as well. For example, Tamibarotene (Osaka City University)178 and Isotretinoin (Oxford University Hospital)179 both drugs are widely used to treat inflammation of the sebaceous glands. The proposed mechanism of action of these drugs is probably related to retinoid receptors in the CNS.180 Phase II trials for both drugs have recently completed but the results of these tests are not yet disclosed. Based on the epidemiological results showing a reduced number of AD cases in patient cohorts with prolonged statins treatments181 that are originally aimed at lowering cholesterol levels (low density lipoprotein) in the blood, clinical trials were initiated for this class of compounds in AD patients. From 2004 to 2012, AD patients were enrolled into several clinical trials involving statins: Pitavastatin (Kowa),182 Atorvastatin (or also known as Lipitor) developed by Pfizer,183, 184 and Simvastatin (NIA).185, 186 However, there were no significant positive results obtained so far.187 Yet, University of Massachusetts in 2015 initiated phase II for Simvastatin in combination with L-arginine and tetrahydrobiopterin. The parallel phase IV for statins in patients with mild cognitive impairment (Charite University, Berlin) is also in progress. Additionally, there are studies involving a group of drugs acting on insulin homeostasis. Namely, Humulin RU-100 (NIH) recombinant short-acting human insulin consisting of zinc-insulin crystals dissolved in a clear fluid with intranasal injections188, 189 ; Insulin detemir Medicinal Research Reviews DOI 10.1002/med

1208


Figure 10. Available structures for other drugs including antioxidants and compounds with undisclosed targets or mechanisms of action.

(Levemir/Levemir300) is a long-acting insulin analog190 ; Liraglutide (Imperial College)191 and Exenatide (NIH)192 are both recombinant peptide agonists of the human glucagon-like peptide1 (amino acids 7–37); and MSDC-0160 (Metabolic Solutions), which was originally developed for type 2 diabetes treatments.193 Pioglitazone hydrochloride is an orally active insulin sensitizer and the product is in phase III clinical trials at Takeda for the prevention of mild cognitive impairment due to AD in combination with TOMM40 biomarker assay.194 An additional seven drugs are in phase II by companies that are not disclosing their structures or mechanism of action. These drugs include the following: LND-101001 (Lupin),195 MK-7622 (Merck & Co.),196, 197 JNJ-54861911 (Janssen Research & Development),64 AVN397198 and AVN-101199 (both by Avineuro), and a herbal drug RPh-201 (Regenera Pharma).200 Medicinal Research Reviews DOI 10.1002/med


Figure 11.

r 1209

Launched drugs for treatment of Alzheimer’s disease.

Available structures for other drugs including antioxidants and compounds with undisclosed targets or mechanisms of action are listed in Figure 10. The overall list of agents at different stages of clinical trials is presented in Tables I-III each according to the corresponding phase.

3. MEDICINES LAUNCHED EARLIER FOR AD TREATMENTS The pharmacotherapy of AD includes four main drugs that are most often used nowadays (Fig. 11): Aricept (Donepezil), Rivastigmine (Exelon), Galantamine (Reminyl), and Memantine (Namenda, Nougaro, etc.). However, it is necessary to note that a number of other drugs have been developed as AD therapeutics and/or for other forms of dementia which are now used less frequently. In 1986, Takeda had registered Idebenone (Mnesis) as a highly effective antioxidant trap of free radicals for oral use in treatment of Alzheimer’s-type dementia.201 Currently, the drug is also used to treat other pathologies. In 2015, it was reported in treatments of Duchenne muscular dystrophy. In the mid-1980s, the original drug Ipidacrine (Ipidacrinum, Neuromedin, Amiridine, Amiridinum) was developed by the Russian National Research Center for Biologically Active Compounds and since the 1990s it has been approved as a learning and memory stimulator for the treatment of AD as well as other forms of senile dementia, and for treatment of children experiencing learning difficulties in minimal cerebral dysfunction.202 The distribution license for Amiridine (NIK-247) in Japan belongs to Nikken. Structurally related to tacrine, amiridin significantly lowers toxicity, particularly hepatotoxicity. Xel Pharmaceuticals developed Huperzine (Hupersine A, Cerebra),203 which is a herbal alkaloid and acts as an inhibitor of AChE and an NMDAR antagonist. It is currently widely used in China for AD treatments. At the present time, the drug is in phase I in AD patients in the form of a skin applicator. Medicinal Research Reviews DOI 10.1002/med

1210


4. CONCLUSIONS Analysis of modern approaches in research and development of new efficient drugs for treatment of AD identifies the following key trends: 1. Development of compounds acting on the main stages of pathogenesis of the disease — disease-modifying drugs These drugs could potentially slow the development of structural and functional abnormalities in the CNS providing sustainable improvements of cognitive functions (in the case of AD) persisting even after the drug withdrawal.204 In the case of AD treatments, the main directions include the search for drugs that are aimed at reducing and promoting removal of the main pathological structures — Aβ aggregates and NFTs formed by hyperphosphorylated Tau. Of considerable interest is the development and validation of new molecular targets and pathways that are involved in the pathogenesis of the disease. Major attention is drawn to molecular targets and enzymes causing the formation and degradation of Aβ peptide (beta-, gamma-, and alpha-secretases) as well as the enzymes involved in the phosphorylation of Tau (Cdk-5, glycogen synthase 3β [GSK3β], c-Jun N-terminal kinase [JNK], and others). The possibilities of pharmacological correction of the ApoE system as a way of removing pathogenic Aβ oligomers are particularly compelling. A rise of promising approaches of pharmacological correction of AD has emerged in past years. These include stabilization of mitochondrial function (mitoprotectors), inhibition of pathological protein aggregation in NDD (drugs preventing proteinopathy), and activation of endogenous cell clearance systems by stimulating autophagy and neurogenesis. As a result, several different potent groups of compounds were proposed utilizing these mechanisms in model systems. Most such compounds are still in the very early stages of clinical trials or on preclinical trials. 2. Multitargeted drugs The multifactor nature of AD is commonly recognized, implying the involvement of a number of neurobiological targets (including the Aβ peptide and Tau protein) in the formation of this neurodegenerative disease. In this context, the concept of multitarget drugs having an integrated action on a number of biological targets involved in pathogenesis of the disease appears to be highly promising in the design of drugs for treating AD. It can be expected that these drugs would be able not only to compensate for or restore the lost cognitive functions, but also to suppress further development of the neurodegenerative process. These include the combinational approaches where a single structure possess inhibitory properties of cholinesterase and monoamine oxidase, antioxidant and metallo-chelate properties, the ability to act as ligands for multiple receptors, and incorporation of additional NO-generating fragments into the ligand core structure. 3. Repositioning of old drugs Research and development of new drugs is a long-term (10–15 years), expensive (hundreds of millions of dollars), and risky process. In the field of AD treatments, over the last decade more than 50 drug candidates have successfully passed phase II but none have passed phase III. The main reasons are believed to be a lack of knowledge of the mechanism(s) of disease development (which are often a close group of pathologies with different etiology) as well as obstacles of modeling complex human NDD in animals. In this regard, opportunities for use of existing drugs for new applications are opening a very attractive approach to facilitate completion of clinical trials. Such a “repositioning”205 of the existing medications appears extremely efficient Medicinal Research Reviews DOI 10.1002/med


r 1211

from the investment point of view as it minimizes the risk of unknown side effects shortening total time of clinical trials due to known safety characteristics of these medicines. Interestingly, the successful application of known drugs for the treatment of NDD sometimes leads to the discovery of new pharmacological targets as in the case of Bexarotene or Dimebon. Since the last anti-Alzheimer’s agent, Memantine, was launched in 2003, more than 500 clinical trials have been conducted for AD treatment. More than 50 compounds successfully passed phase II clinical trials, but failed in phase III. In this regard, the question of possible reasons of fatal fails of late stages of AD drugs clinical trials are actively discussed in numerous reviews and research articles.2, 206 One possible reason might be linked to the heterogeneous nature of AD pathology.207, 208 These considerations had led to a paradoxical conclusion that larger clinical trials containing more diverse patient population are not always better. Indeed, in such a population it could be harder to find a sign of efficacy for a drug that works only (or mainly) against a certain form or stage of disease. Subgroup comparisons can in principle point to the real treatment effects, which may then be confirmed by further studies of those subgroups. This logic was used by Eli Lilly developing the antiamyloid agent Solanezumab — an antibody designed to bind and promote clearance of the β-amyloid protein. In two previous trials of Solanezumab, called EXPEDITION and EXPEDITION II, Eli Lilly used a cognitive test and a functional measurement to track the response of people with both mild and moderate AD. Both trials failed to show significant benefits over the placebo in either measurement. Combing through data from the second trial, however, Eli Lilly noticed that participants with mild AD seemed to do better than controls in the cognitive portion of the testing. That led the company to its current billion-dollar gamble on a study of roughly 2100 people with the mild AD patients alone, which will conclude in October 2016. Another quite unexpected reason is also linked to the problem of heterogeneous patient population in trials, lies in different sensitivity to specific agents of patients that have been treated before or not treated by another drug. In clinical trails with LMTX (leucomethylthioniniumsalt) initiated by TauRx company, it was noted that the subset of patients who were not taking other AD drugs performed better on LMTX. “It turned out the drug only worked if people were not taking other drugs”, TauRx’s chief executive, Claude Wischik, said in an interview.209 Even different gender ratio in groups of patients could lead to deviations in results of clinical trials as it was recently noted that women’s better verbal memory skills may mask early signs of AD.210 The important problem that hamper development of efficient agents for treatment of AD lies in a limited number and narrow application of animal models recapitulating major features of AD. An Alzheimer’s expert at the Mayo Clinic, Mayo’s D. Knopman, stated that such models “have not been very good at predicting a drug’s effect, and none of them is appropriate for late-onset Alzheimer’s” as opposed to the uncommon early-onset form that results from rare genetic mutations.211 A quite exhausted list of challenges and problems in clinical trials for AD is summarized in the review by Mangialasche et al.212 Notwithstanding the fact that no new drugs for AD treatment have been launched on the market in the past 12 years, the active research for promising new structures that are capable of preventing the progression of the disease is still ongoing. A number of radically new approaches for targeting key stages in AD pathogeneses were proposed, giving hope for success in developing new therapeutics for AD treatments in the coming years.

5. ABBREVIATIONS 5-HT = 5-hydrotryptamine 5-HT6R = 5-hydroxytryptamine receptor 6 Aβ = beta-amyloid Medicinal Research Reviews DOI 10.1002/med

1212


ACh AChE AChEI AD AMPAR ApoE APP BuChE CSF GABA ChEI GluR IgG MCI nAChR NFL NFT NMDA NMDAR PD PDE TNF

= = = = = = = = = = = = = = = = = = = = = =

acetylcholine acetylcholinesterase acetylcholinesterase inhibitor Alzheimer’s disease α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors apolipoprotein E amyloid precursor protein butyrylcholinesterase cerebrospinal fluid gamma-aminobutyric acid cholinesterase inhibitors glutamate receptor immunoglobulin G mild cognitive impairment nicotinic acetylcholine receptor neurofilament protein neurofibrillary tangles N-methyl-D-aspartate N-methyl-D-aspartate receptor Parkinson’s disease phosphodiesterase tumor necrosis factor

ACKNOWLEDGMENT This work was supported by grant number 14-23-00160 from the Russian Scientific Foundation. For critical suggestions and discussion the authors greatly thank Dr. Dennis McQuerry and Dr. Maureen McQuerry. REFERENCES 1. Skripka-Serry J. The great neuro-pipeline brain drain (and why Big Pharma hasn’t given up on CNS disorders. 2013. http://www.ddw-online.com/therapeutics/p216813-the-great-neuropipeline-brain-drain-(and-why-big-pharma-hasn-t-given-up-on-cns-disorders)-fall-13.html. 2. Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: Few candidates, frequent failures. Alzheimers Res Ther 2014;6(4):37. 3. Kukharsky MS, Ovchinnikov RK, Bachurin SO. [Molecular aspects of the pathogenesis and current approaches to pharmacological correction of Alzheimer’s disease]. Zh Nevrol Psikhiatr Im SS Korsakova 2015;115(6):103–114. 4. Nussbaum JM, Seward ME, Bloom GS. Alzheimer disease: A tale of two prions. Prion 2014;7(1):14– 19. 5. Carreiras MC, Mendes E, Perry MJ, Francisco AP, Marco-Contelles J. The multifactorial nature of Alzheimer’s disease for developing potential therapeutics. Curr Top Med Chem 2013;13(15):1745– 1770. 6. De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV. Alzheimer’s disease. Subcell Biochem 2012;65:329–352. 7. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: An appraisal for the development of therapeutics. Nat Rev Drug Discov 2011;10(9):698–712. Medicinal Research Reviews DOI 10.1002/med


r 1213

8. Maccioni RB, Farias G, Morales I, Navarrete L. The revitalized tau hypothesis on Alzheimer’s disease. Arch Med Res 2010;41(3):226–231. 9. Sorbi S. Molecular genetics of Alzheimer’s disease. Aging 1993;5(6):417–425. 10. Armstrong RA. What causes Alzheimer’s disease? Folia Neuropathol 2013;51(3):169–188. 11. Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM. Alzheimer’s disease. Lancet 2016;388(10043):505–517. 12. Bradley WG. Alzheimer’s disease: Theories of causation. Adv Exp Med Biol 1990;282:31–38. 13. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 1996;17(5):1005–1013. 14. Chartier-Harlin MC, Crawford F, Hamandi K, Mullan M, Goate A, Hardy J, Backhovens H, Martin JJ, Broeckhoven CV. Screening for the beta-amyloid precursor protein mutation (APP717: Val—Ile) in extended pedigrees with early onset Alzheimer’s disease. Neurosci Lett 1991;129(1):134–135. 15. Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, Bird TD, Schellenberg GD. A familial Alzheimer’s disease locus on chromosome 1. Science 1995;269(5226):970–973. 16. Sisodia SS, Kim SH, Thinakaran G. Function and dysfunction of the presenilins. Am J Hum Genet 1999;65(1):7–12. 17. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: Identification as the microtubule-associated protein tau. Proc Natl Acad Sci USA 1988;85(11):4051–4055. 18. Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988;85(13):4884–4888. 19. Olsson B, Lautner R, Andreasson U, Ohrfelt A, Portelius E, Bjerke M, Holtta M, Rosen C, Olsson C, Strobel G, Wu E, Dakin K, Petzold M, Blennow K, Zetterberg H. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: A systematic review and meta-analysis. Lancet 2016;15(7):673– 684. 20. Glenner GG, Wong CW, Quaranta V, Eanes ED. The amyloid deposits in Alzheimer’s disease: Their nature and pathogenesis. Appl Pathol 1984;2(6):357–369. 21. Selkoe DJ. Alzheimer’s disease: A central role for amyloid. J Neuropathol Exp Neurol 1994;53(5):438–447. 22. Khlistunova I, Biernat J, Wang Y, Pickhardt M, von Bergen M, Gazova Z, Mandelkow E, Mandelkow EM. Inducible expression of Tau repeat domain in cell models of tauopathy: Aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem 2006;281(2):1205–1214. 23. Walsh DM, Selkoe DJ. A beta oligomers – A decade of discovery. J Neurochem 2007;101(5):1172– 1184. 24. Querfurth HW, LaFerla FM. Alzheimer’s disease. New Engl J Med 2010;362(4):329–344. 25. Gavrilova SI, Seleznyova ND, Roschina IF, Fedorova YaB. [Early diagnosis of Alzheimer’s disease on the pre-dementia stages and its therapy] In Russian. Moscow: Nauchniy mir. 2014; p. 95–124 26. Friedland-Leuner K, Stockburger C, Denzer I, Eckert GP, Muller WE. Mitochondrial dysfunction: Cause and consequence of Alzheimer’s disease. Prog Mol Biol Transl Sci 2014;127:183–210. 27. Raskin J, Cummings J, Hardy J, Schuh K, Dean RA. Neurobiology of Alzheimer’s disease: Integrated molecular, physiological, anatomical, biomarker, and cognitive dimensions. Curr Alzheimer Res 2015;12(8):712–722. 28. Tipping KW, van Oosten-Hawle P, Hewitt EW, Radford SE. Amyloid fibres: Inert end-stage aggregates or key players in disease? Trends Biochem Sci 2015;40(12):719–727. 29. Iqbal K, Liu F, Gong CX. Tau and neurodegenerative disease: The story so far. Nat Rev 2016;12(1):15–27.


1214


30. Nordberg A. Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease. Alzheimer Dis Assoc Disord 2006;20(2 Suppl 1):S12–18. 31. Chalmers KA, Wilcock GK, Vinters HV, Perry EK, Perry R, Ballard CG, Love S. Cholinesterase inhibitors may increase phosphorylated tau in Alzheimer’s disease. J Neurol 2009;256(5):717–720. 32. Danysz W, Parsons CG, Mobius HJ, Stoffler A, Quack G. Neuroprotective and symptomatological action of memantine relevant for Alzheimer’s disease – A unified glutamatergic hypothesis on the mechanism of action. Neurotox Res 2000;2(2-3):85–97. 33. Danysz W, Parsons CG. Alzheimer’s disease, beta-amyloid, glutamate, NMDA receptors and memantine – Searching for the connections. Br J Pharmacol 2012;167(2):324–352. 34. Mohandas E, Rajmohan V, Raghunath B. Neurobiology of Alzheimer’s disease. Indian J Psychiatry 2009;51(1):55–61. 35. Hemming ML, Selkoe DJ. Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem 2005;280(45):37644–37650. 36. Zhang Y, McLaughlin R, Goodyer C, LeBlanc A. Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons. J Cell Biol 2002;156(3):519– 529. 37. Laske C. Phase 3 trials of solanezumab and bapineuzumab for Alzheimer’s disease. New Engl J Med 2015;370(15):1459. 38. Lachno DR, Evert BA, Vanderstichele H, Robertson M, Demattos RB, Konrad RJ, Talbot JA, Racke MM, Dean RA. Validation of assays for measurement of amyloid-beta peptides in cerebrospinal fluid and plasma specimens from patients with Alzheimer’s disease treated with solanezumab. J Alzheimers Dis 2013;34(4):897–910. 39. Sevigny J, Chiao P, Williams L, Chen T, Ling Y, O’Gorman J, Hock C, Nitsch RM, Sandrock A. Aducanumab (BIIB037), an anti-amyloid beta monoclonal antibody, in patients with prodromal or mild Alzheimer’s disease: Interim results of a randomized, double-blind, placebo-controlled, phase 1b study. Alzheimers Dement 2015;11(7):P277. 40. Jacobsen H, Ozmen L, Caruso A, Narquizian R, Hilpert H, Jacobsen B, Terwel D, Tanghe A, Bohrmann B. Combined treatment with a BACE inhibitor and anti-Abeta antibody gantenerumab enhances amyloid reduction in APPLondon mice. J Neurosci 2014;34(35):11621–11630. 41. Relkin N. Clinical trials of intravenous immunoglobulin for Alzheimer’s disease. J Clin Immunol 2014;34 Suppl 1:S74–79. 42. Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging 2009;30(11):1728–1736. 43. Baxalta. Phase III efficacy, safety, and tolerability study of HYQVIA/HyQvia and GAMMAGARD LIQUID/KIOVIG in CIDP (NCT02549170). 2012. https://clinicaltrials.gov/ct2/ show/NCT02549170. 44. Liu E, Schmidt ME, Margolin R, Sperling R, Koeppe R, Mason NS, Klunk WE, Mathis CA, Salloway S, Fox NC, Hill DL, Les AS, Collins P, Gregg KM, Di J, Lu Y, Tudor IC, Wyman BT, Booth K, Broome S, Yuen E, Grundman M, Brashear HR. Amyloid-beta 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials. Neurology 2015;85(8):692–700. 45. Hu C, Adedokun O, Ito K, Raje S, Lu M. Confirmatory population pharmacokinetic analysis for bapineuzumab phase 3 studies in patients with mild to moderate Alzheimer’s disease. J Clin Pharmacol 2015;55(2):221–229. 46. Jarvis LM. The next chapter in treating Alzheimer’s. Chem Eng News ACS 2015;93(22):11–15. 47. Schneeberger A, Mandler M, Otawa O, Zauner W, Mattner F, Schmidt W. Development of AFFITOPE vaccines for Alzheimer’s disease (AD) – from concept to clinical testing. J Nutr Health Aging 2009;13(3):264–267. 48. PR Newswire. Breakthrough in Alzheimer’s disease: AFFiRiS halted clinical progression in Alzheimer patients upon treatment with AD04 in a phase ii clinical study. 2014. http://www.prnewswire.com/news-releases/breakthrough-in-alzheimers-disease-affiris-haltedMedicinal Research Reviews DOI 10.1002/med


49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

r 1215

clinical-progression-in-alzheimer-patients-upon-treatment-with-ad04-in-a-phase-ii-clinical-study261788511.html. ¨ Schneeberger A, Hendrix S, Ellison N, Burger V, Dubois B. Additional results from a phase II study to assess the clinical and immunological activity, safety, and tolerability of AFFITOPE ad02 in patients with early Alzheimer’s disease (AD). Alzheimer’s & Dementia: J Alzheimer’s Assoc. 2015;11(7):P276. Hickman DT, Lopez-Deber MP, Ndao DM, Silva AB, Nand D, Pihlgren M, Giriens V, Madani R, St-Pierre A, Karastaneva H, Nagel-Steger L, Willbold D, Riesner D, Nicolau C, Baldus M, Pfeifer A, Muhs A. Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases. J Biol Chem 2011;286(16):13966– 13976. Tucker S, Moller C, Tegerstedt K, Lord A, Laudon H, Sjodahl J, Soderberg L, Spens E, Sahlin C, Waara ER, Satlin A, Gellerfors P, Osswald G, Lannfelt L. The murine version of BAN2401 (mAb158) selectively reduces amyloid-beta protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis 2015;43(2):575–588. Wang CY, Finstad CL, Walfield AM, Sia C, Sokoll KK, Chang TY, Fang XD, Hung CH, HutterPaier B, Windisch M. Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer’s disease. Vaccine 2007;25(16):3041–3052. United Neuroscience Ltd. Evaluate the safety, tolerability, immunogenicity and efficacy of UB-311 in mild Alzheimer’s disease (AD) patients (NCT02551809). 2015. https://clinical trials.gov/ct2/show/NCT02551809. Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K, Lohmann S, Piorkowska K, Gafner V, Atwal JK, Maloney J, Chen M, Gogineni A, Weimer RM, Mortensen DL, Friesenhahn M, Ho C, Paul R, Pfeifer A, Muhs A, Watts RJ. An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci 2012;32(28):9677–9689. Landen JW, Zhao Q, Cohen S, Borrie M, Woodward M, Billing CB Jr., Bales K, Alvey C, McCush F, Yang J, Kupiec JW, Bednar MM. Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: A phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clin Neuropharmacol 2013;36(1): 14–23. Dodel R, Rominger A, Blennow K, Barkhof F, Wietek S, Haag S, Bartenstein P, Farlow M, Jessen F. A randomized, double-blind, placebo-controlled dose-finding trial of intravenous immunoglobulin R 10%,Octapharma AG) in patients with mild to moderate Alzheimer’s disease (IVIG; Octagam (GAM10-04). Alzheimers Dement 2011;7(4):e55–e56. Pradier L, Cohen C, Blanchard V, Debeir T, Barneoud P, Canton T, Menager J, Bohme A, Rooney T, Guillet M, Cameron B, Shi Y, Naimi S, Ravetch J, Claudel S, Alam J. SAR228810: An antiprotofibrillar beta-amyloid antibody designed to reduce risk of amyloid-related imaging abnormalities (ARIA) Alzheimer’s & Dementia: J Alzheimer’s Assoc. 2013;9(4):P808–P809. Rosen L, Pomfret M, Billinton A, Chessell I, Chessell T, Kugler A, Lindqvist E, McFarlane M, Groves M, Narwal R, Tan K, Tatipalli M, Dudley A. Tolerability and preliminary pharmacodynamics after single doses of MEDI1814, a beta-amyloid 42 (Aß42)-specific antibody, in mild-moderate Alzheimer’s disease. J Prevent Alzheimers Dis. 2015;2(4):287. KHK Pharma. A study of single and multiple doses of KHK6640 in subjects with prodromal or mild to moderate Alzheimer’s disease (NCT02127476). 2014. https://clinicaltrials.gov/ct2/show/ study/NCT02127476. Davtyan H, Ghochikyan A, Petrushina I, Hovakimyan A, Davtyan A, Poghosyan A, Marleau AM, Movsesyan N, Kiyatkin A, Rasool S, Larsen AK, Madsen PJ, Wegener KM, Ditlevsen DK, Cribbs DH, Pedersen LO, Agadjanyan MG. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: Prelude to a clinical trial. J Neurosci 2013;33(11):4923–4934.


1216


61. Zhou B, Rothlein R, Shen J, Valcarce C, Selmer J, Hanhan M, Kindy MS, Mjalli AMM, Kostura MJ. TTP4000, a soluble fusion protein inhibitor of Receptor for Advanced Glycation End Products (RAGE) is an effective therapy in animal models of Alzheimer?’s disease. The FASEB Journal 2013;27(1 Supplement):803.801. 62. Yan R, Vassar R. Targeting the beta secretase BACE1 for Alzheimer’s disease therapy. Lancet 2014;13(3):319–329. 63. Alexander R, Budd S, Russell M, Kugler A, Cebers G, Ye N, Olsson T, Burdette D, Maltby J, Paraskos J, Elsby K, Han D, Goldwater R, Ereshefsky L. AZD3293 A novel BACE1 inhibitor: safety, tolerability, and effects on plasma and CSF amyloid-beta peptides following single- and multiple-dose administration. Neurobiology of Aging 2014;35:S2. 64. Neumann U, Rueeger H, Machauer R, Veenstra SJ, Lueoend RM, Tintelnot-Blomley M, Laue G, Beltz K, Vogg B, Schmid P, Frieauff W, Shimshek DR, Staufenbiel M, Jacobson LH. A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-beta and neuroinflammation in APP transgenic mice. Mol Neurodegener 2015;10:44. 65. Matijevic M, Watanabe H, Sato Y, Bernier F, McGrath S, Burns L, Yamamoto N, Ogo M, Dezso Z, Chow J, Oda Y, Kaplow J, Albala B. A single dose of the beta-secretase inhibitor, e2609, decreases CSF bace1 enzymatic activity in cynomolgus monkeys. Alzheimers Dement 2015;11(7):P841. 66. Nicolas L, Kammerer K-P, Schaible J, Link J, Kleiner O, Borta A, Podhorna J, Scholpp J. Pharmacokinetics, pharmacodynamics, and safety of the novel bace inhibitor bi1181181 after oral administration of single ascending doses in healthy subjects. Alzheimers Dement 2015;11(7):P740–P741. 67. FORUM Pharmaceuticals. Safety, tolerability, pharmacokinetics of EVP-0962 and effects of EVP-0962 on cerebral spinal fluid amyloid concentrations in healthy subjects and in subjects with mild cognitive impairment or early Alzheimer’s disease (NCT01661673). 2014. https://clinicaltrials.gov/ct2/show/NCT01661673. 68. Navarro D, Castaner R, Fernandez-Forner D. NME digest. Drugs Future 2015;40(10):667. 69. AZTherapies . Safety and efficacy study of ALZT-OP1 in subjects with evidence of early Alzheimer’s disease (NCT02547818). 2015. https://clinicaltrials.gov/ct2/show/NCT02547818. 70. Shanghai Green Valley Pharmaceutical. Safety, efficacy and dose titration of sodium oligomannurarate capsule on mild to moderate Alzheimer’s disease (NCT01453569). 2014. https:// clinicaltrials.gov/ct2/show/NCT01453569. 71. Maccecchini ML, Chang MY, Pan C, John V, Zetterberg H, Greig NH. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-beta peptide and tau levels: Target engagement, tolerability and pharmacokinetics in humans. J Neurol Neurosurg Psychiatry 2012;83(9):894– 902. 72. Sinha S, Du Z, Maiti P, Klarner FG, Schrader T, Wang C, Bitan G. Comparison of three amyloid assembly inhibitors: The sugar scyllo-inositol, the polyphenol epigallocatechin gallate, and the molecular tweezer CLR01. ACS Chem Neurosci 2012;3(6):451–458. 73. Transition Therapeutics. Transition therapeutics announces results of data analysis from ELND005 phase 2/3 clinical study in agitation and aggression in Alzheimer’s disease patients. 2015. http:// www.transitiontherapeutics.com/media/press_releases/20151015.pdf. 74. Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, Lovat LB, Bartfai T, Alanine A, Hertel C, Hoffmann T, Jakob-Roetne R, Norcross RD, Kemp JA, Yamamura K, Suzuki M, Taylor GW, Murray S, Thompson D, Purvis A, Kolstoe S, Wood SP, Hawkins PN. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 2002;417(6886):254–259. 75. Suhr OB, Lundgren E, Westermark P. Transthyretin amyloidoses: New strategies for therapeutic intervention. Drugs Future 2010;35(4):325. 76. BELLUS. BELLUS Health announces partnership for the development of BLU8499. 2012. http://www.bellushealth.com/English/investors-and-news/press-releases/press-release -details/2012/BELLUS-Health-Announces-Partnership-for-the-Development-ofBLU84991130839/default.aspx. Medicinal Research Reviews DOI 10.1002/med


r 1217

77. Vartiainen NE, Williams M, Charles ML, Stenius T, Nurmi A, Yrjanheikki J. SAN-61 protects against Ab1-42, OGD and H2O2 in rat mixed cortical cultures and inhibits GSK3b (Abst. 336.16/L15). Society for Neuroscience Meeting. 2009. Abstract available online: http://www.abstractsonline.com/plan/ViewAbstract.aspx?cKey=f92bb357-e664-4d76-853968c8c1c397f9&mID=2285&mKey=%7b081F7976-E4CD-4F3D-A0AF-E8387992A658% 7d&sKey=2d44ed6c-0abc-4592-9d1b-722055d310ef. 78. Hu Q, Cam J, Lake T, Cummings J, Esposito L, Yadon M-C, Snow A. Identification of Exebryl-1 and other novel small molecules as tau protein aggregation inhibitors. Alzheimer’s & Dementia: J Alzheimer’s Assoc. 2011;7(4):S481. 79. Brunden KR, Trojanowski JQ, Lee VM. Advances in tau-focused drug discovery for Alzheimer’s disease and related tauopathies. Nat Rev Drug Discov 2009;8(10):783–793. 80. Valera E, Spencer B, Masliah E. Immunotherapeutic Approaches Targeting Amyloid-beta, alpha-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics 2016;13(1):179–189 81. Novak M. Tau vaccine: Active immunization with misfolded tau protein attenuates tau pathology in the transgenic rat model of tauopathy. Alzheimer’s & Dementia: J Alzheimer’s Assoc. 2009;5(4):P93. 82. Sheridan C. Pivotal trials for beta-secretase inhibitors in Alzheimer’s. Nat Biotechnol 2015;33(2):115–116. 83. Riedmann EM. Swiss biotech firm starts first trial of a tau-targeting Alzheimer vaccine. Hum Vacc Immunother 2014;10(3):531. 84. Bristol-Myers Squibb. A randomized, double-blind, placebo-controlled, single ascending dose study of intravenously administered BMS-986168 in healthy subjects (NCT02294851). 2014. https://clinicaltrials.gov/ct2/show/NCT02294851. 85. Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci USA 1996;93(20):11213– 11218. 86. Wischik CM, Staff RT, Wischik DJ, Bentham P, Murray AD, Storey JM, Kook KA, Harrington CR. Tau aggregation inhibitor therapy: An exploratory phase 2 study in mild or moderate Alzheimer’s disease. J Alzheimers Dis 2015;44(2):705–720. 87. Fox P. Cognitive and functional connectivity effects of methylene blue in healthy aging, mild cognitive impairment and Alzheimer’s disease (MB2) (NCT02380573). 2015. https://clinical trials.gov/ct2/show/NCT02380573. 88. Baddeley TC, McCaffrey J, Storey JM, Cheung JK, Melis V, Horsley D, Harrington CR, Wischik CM. Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer’s disease. J Pharmacol Exp Ther 2015;352(1):110– 118. 89. Panza F, Solfrizzi V, Seripa D, Imbimbo BP, Lozupone M, Santamato A, Zecca C, Barulli MR, Bellomo A, Pilotto A, Daniele A, Greco A, Logroscino G. Tau-centric targets and drugs in clinical development for the treatment of Alzheimer’s disease. BioMed Res Int 2016;2016: 15. 90. Muggia F, Kudlowitz D. Novel taxanes. Anticancer Drugs 2014;25(5):593–598. 91. Ramirez MJ, Lai MK, Tordera RM, Francis PT. Serotonergic therapies for cognitive symptoms in Alzheimer’s disease: Rationale and current status. Drugs 2014;74(7):729–736. 92. Wilkinson D, Windfeld K, Colding-Jorgensen E. Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer’s disease (LADDER): A randomised, double-blind, placebo-controlled phase 2 trial. Lancet 2014;13(11):1092–1099. 93. Maher-Edwards G, Dixon R, Hunter J, Gold M, Hopton G, Jacobs G, Hunter J, Williams P. SB742457 and donepezil in Alzheimer disease: A randomized, placebo-controlled study. Int J Geriatr Psychiatry 2011;26(5):536–544. 94. Daripelli S, Bhyrapuneni G, Mudigonda K, Benade V, Ayyanki G, Kamuju V, Ponnamaneni R, Manoharan A, Nirogi R. Novel 5-HT6 antagonist, SUVN-502 potentiates the Medicinal Research Reviews DOI 10.1002/med

1218

95.

96.

97.

98. 99.

100.

101.

102. 103.

104.

105.

106.

107.

108.

r BACHURIN, BOVINA, AND USTYUGOV effects of donepezil on neurochemical and electrophysiological activity in rat hippocampus (Abst. 761.11). Society for Neuroscience Meeting. 2015. Abstract available online: http://www.abstractsonline.com/plan/ViewAbstract.aspx?cKey=bf2cda8b-19a9-477b-829a29ea4c5aaa87&mID=3744&mKey=d0ff4555-8574-4fbb-b9d4-04eec8ba0c84&sKey=581d50eb8d87-43d0-ab59-0f253e8c9e30. Tkachenko S, Ivachtchenko A, Khvat A, Okun I, Lavrovsky Y, Salimov R. Discovery and preclinical studies of AVN-322 highly selective and potent 5HT6 antagonist for cognition enhancement in treating neurodegerative diseases. 2009. Abstract available online: http://www.karger.com/ ProdukteDB/miscArchiv/NDD_2009_006_s_1/pdf/945.pdf. Kwon S, Rajagopal L, Huang M, Michael E, Meltzer H. RP5063 reverses and prevents sub-chronic phencyclidine-induced declarative memory deficits and increased dopamine efflux in the prefrontal cortex region in C57BL/6J mice (Abst/823.04). Society for Neuroscience Meeting. 2015. Abstract available online: http://www.abstractsonline.com/plan/ViewAbstract. aspx?cKey=43ca0d8f-ec97-4d1d-b215-94312a182bfb&mID=3744&mKey=d0ff4555-8574-4fbbb9d4-04eec8ba0c84&sKey=b0f5ac8e-9e1b-453c-be9d-378790a1281e. Thomsen MS, Andreasen JT, Arvaniti M, Kohlmeier KA. Nicotinic acetylcholine receptors in the pathophysiology of Alzheimer’s disease: The role of protein-protein interactions in current and future treatment. Curr Pharm Des 2016;22(14):2015–2034. Lombardo S, Maskos U. Role of the nicotinic acetylcholine receptor in Alzheimer’s disease pathology and treatment. Neuropharmacology 2013;96(Pt B):255–262. Othman A, Meier A, Ritchie CW, Florian H, Gault LM, Tang Q. Efficacy and safety of the alpha7 agonist abt-126 as a monotherapy treatment in mild-to-moderate alzheimer’s dementia: results of a phase 2b trial. Alzheimers Dement 2014;10(4):P137. Frolich L, Ashwood T, Nilsson J, Eckerwall G. Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer’s disease: a phase IIb dose-finding study. J Alzheimers Dis 2011;24(2):363–374. Greenamyre JT, Maragos WF, Albin RL, Penney JB, Young AB. Glutamate transmission and toxicity in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 1988;12(4):421– 430. Nakamura T, Lipton SA. Protein S-nitrosylation as a therapeutic target for neurodegenerative diseases. Trends Pharmacol Sci 2016;37(1):73–84. Avanir. Avanir Pharmaceuticals announces initiation of phase ii study of AVP-786 for the adjunctive treatment of major depressive disorder. 2014. http://www.prnewswire.com/news-releases/avanirpharmaceuticals-announces-initiation-of-phase-ii-study-of-avp-786-for-the-adjunctive-treatmentof-major-depressive-disorder-272700931.html. Chumakov I, Nabirotchkin S, Cholet N, Milet A, Boucard A, Toulorge D, Pereira Y, Graudens E, Traore S, Foucquier J, Guedj M, Vial E, Callizot N, Steinschneider R, Maurice T, Bertrand V, Scart-Gres C, Hajj R, Cohen D. Combining two repurposed drugs as a promising approach for Alzheimer’s disease therapy. Sci Rep 2015;5:7608. Lin CH, Chen PK, Chang YC, Chuo LJ, Chen YS, Tsai GE, Lane HY. Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: A randomized, double-blind, placebo-controlled trial. Biol Psychiatry 2014;75(9):678–685. Grigoriev VV, Proshin AN, Kinzirsky AS, Bachurin S. Modern approaches to the design of memory and cognitive function stimulants based on AMPA receptor ligands. Russ Chem Rev 2009;78(5): 485. Louis C, Danober L, Carrié I, Dumas N, Albinet K, Llopis K, Roger A, Gandon M-H, Hugot A, Krentner M, Thomas J-Y, Rogez N, Vandesquille M, Krazem A, Béracochéa D, Bertainaanglade V, Drieu la rochelle C, Junges C, Bertrand M, Billiald S, Tordjman C, Cordi A, Lestage P. In vivo pharmacological profile of S47445, a novel positive allosteric modulator of AMPA- type glutamate receptors. Neurodegenerative Diseases 2015;15(s1):p365. Mandavilli A. The amyloid code. Nat Med 2006;12(7):747–751.



r 1219

109. Piette F, Belmin J, Vincent H, Schmidt N, Pariel S, Verny M, Marquis C, Mely J, Hugonot-Diener L, Kinet JP, Dubreuil P, Moussy A, Hermine O. Masitinib as an adjunct therapy for mild-tomoderate Alzheimer’s disease: A randomised, placebo-controlled phase 2 trial. Alzheimers Res Ther 2011;3(2):16. 110. Lawlor B, Kennelly S, O’Dwyer S, Cregg F, Walsh C, Coen R, Kenny RA, Howard R, Murphy C, Kelly J, Adams J, Daly L, Segurado R, Gaynor S, Crawford F, Mullan M, Lucca U, Banzi R, Pasquier F, Breuilh L, Riepe M, Kalman J, Wallin A, Borjesson-Hanson A, Molloy W, Tsolaki M, Olde Rikkert M. A European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer’s disease. BMJ Open 2015;5:e006364 doi:10.1136/bmjopen-2014006364corr1. 111. Ferguson S, Bishop A, Mouzon B, Phillips J, Crynen G, Reed J, Chaytow H, Mullan M, Mathura V, Mullan M, Crawford F. Time course of inflammatory marker response after TBI (Abst #. 254.07/Z8). Society for Neuroscience Meeting. 2011. Abstract available online: http://www.abstractsonline.com/plan/ViewAbstract.aspx?cKey=85154344-ca2b-494e-a787e1323f81fc1b&mID=2773&mKey=%7b8334BE29-8911-4991-8C31-32B32DD5E6C8% 7d&sKey=d70333de-8bb5-4d9f-8a2c-f5d7e7ea5ef1. 112. Sadek B, Saad A, Sadeq A, Jalal F, Stark H. Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases. Behavioural brain research 2016;312:415–430. 113. Panayi F, Sors A, Bert L. Mechanistic characterization of S 38093, a novel inverse agonist at histamine H3 receptors. Neurodegenerative Diseases 2015;15(s1):p156. 114. Benade VS, Daripelli S, Thentu JB, Manoharan A, Medapati RB, Subramanian R, Mekala VR, Shinde AK, Badange RK, Goyal VK, Pandey SK, Nirogi R. SUVN-G3031, a H3 receptor inverse agonist produces procognitive effects without affecting sleep in preclinical models. Alzheimers Dement 2015;11(7):P475. 115. Yao J, Zhao L, Mao Z, Chen S, Wong KC, To J, Brinton RD. Potentiation of brain mitochondrial function by S-equol and R/S-equol estrogen receptor beta-selective phytoSERM treatments. Brain Res 2013;1514:128–141. 116. Rinne JO, Wesnes K, Hänninen J, Murphy M, Riordan H, Rouru J, Group AS. Safety and efficacy of ORM-12741 on cognitive and behavioral symptoms in patients with Alzheimer’s disease: A randomized, double-blind, proof-of-concept study. J Neurol Sci 2013;333:e322. 117. Lahmy V, Meunier J, Malmstrom S, Naert G, Givalois L, Kim SH, Villard V, Vamvakides A, Maurice T. Blockade of Tau hyperphosphorylation and Abeta(1)(-)(4)(2) generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and sigma(1) receptor agonist, in a nontransgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology 2013;38(9):1706– 1723. 118. Cudkowicz M, Bozik ME, Ingersoll EW, Miller R, Mitsumoto H, Shefner J, Moore DH, Schoenfeld D, Mather JL, Archibald D, Sullivan M, Amburgey C, Moritz J, Gribkoff VK. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med 2011;17(12):1652–1656. 119. Chiu WH, Depboylu C, Hermanns G, Maurer L, Windolph A, Oertel WH, Ries V, Hoglinger GU. Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson’s disease. Neuropharmacology 2015;95:367– 376. 120. Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci USA 2012;109(42):E2895– 2903. 121. Xiao R. Levetiracetam might act as an efficacious drug to attenuate cognitive deficits of Alzheimer’s disease. Curr Top Med Chem 2016;16(5):565–573. 122. Hunsberger HC, Weitzner DS, Rudy CC, Hickman JE, Libell EM, Speer RR, Gerhardt GA, Reed MN. Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression. J Neurochem 2015;135(2):381–394. Medicinal Research Reviews DOI 10.1002/med

1220


123. Sugiyama A, Saitoh A, Inagaki M, Oka J, Yamada M. Systemic administration of riluzole enhances recognition memory and facilitates extinction of fear memory in rats. Neuropharmacology 2015;97:322–328. 124. Blasco H, Mavel S, Corcia P, Gordon PH. The glutamate hypothesis in ALS: Pathophysiology and drug development. Curr Med Chem 2014;21(31):3551–3575. 125. Giacobini E. Therapy of Alzheimer disease: Symptomatic or neuroprotective? J Neural Transm 1994;43:211–217. 126. Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. The Tacrine Study Group. JAMA 1994;271(13):985–991. 127. Lane RM, He Y. Butyrylcholinesterase genotype and gender influence Alzheimer’s disease phenotype. Alzheimers Dement 2013;9(2):e1–73. 128. Furukawa-Hibi Y, Alkam T, Nitta A, Matsuyama A, Mizoguchi H, Suzuki K, Moussaoui S, Yu QS, Greig NH, Nagai T, Yamada K. Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-beta peptide in mice. Behav Brain Res 2011;225(1):222–229. 129. Inestrosa NC, Dinamarca MC, Alvarez A. Amyloid-cholinesterase interactions. Implications for Alzheimer’s disease. FEBS J 2008;275(4):625–632. 130. Macdonald IR, Rockwood K, Martin E, Darvesh S. Cholinesterase inhibition in Alzheimer’s disease: Is specificity the answer? J Alzheimers Dis 2014;42(2):379–384. 131. Froestl W, Muhs A, Pfeifer A. Cognitive enhancers (nootropics). Part 2: Drugs interacting with enzymes. J Alzheimers Dis 2013;33(3):547–658. 132. Bhattacharya S, Maelicke A, Montag D. Nasal application of the galantamine pro-drug memogain slows down plaque deposition and ameliorates behavior in 5X familial Alzheimer’s disease mice. J Alzheimers Dis 2015;46(1):123–136. 133. Weinreb O, Amit T, Bar-Am O, Youdim MB. Ladostigil: A novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer’s disease treatment. Curr Drug Targets 2012;13(4):483–494. 134. Webster S, Pallin D. Discovery of UE2343, a potent inhibitor of 11beta-HSD1 for the treatment of Alzheimer’s disease. 2015. http://adisinsight.springer.com/drugs/800042157. 135. Astellas Pharma Global Development. A positron emission tomography occupancy study using ligand [11C]AS2471907 and following oral dosing of ASP3662 (NCT02194491). 2015. https://clinicaltrials.gov/ct2/show/NCT02194491. 136. Weinreb O, Badinter F, Amit T, Bar-Am O, Youdim MB. Effect of long-term treatment with rasagiline on cognitive deficits and related molecular cascades in aged mice. Neurobiol Aging 2015;36(9):2628–2636. 137. Shaddinger BC, Xu Y, Roger JH, Macphee CH, Handel M, Baidoo CA, Magee M, Lepore JJ, Sprecher DL. Platelet aggregation unchanged by lipoprotein-associated phospholipase A(2) inhibition: Results from an in vitro study and two randomized phase I trials. PloS One 2014;9(1):e83094. 138. GlaxoSmithKline. GSK2647544 RD, DDI in healthy young and elderly volunteers (NCT01978327). 2014. https://clinicaltrials.gov/ct2/show/NCT01978327. 139. Rosenbrock H, Marti A, Koros E, Runge F, Fuchs H, Giovannini R, Dorner-Ciossek C. Improving synaptic plasticity and cognitive function in rodents by the novel phosphodiesterase 9A inhibitor bi 409306. Alzheimers Dement 2015;11:P612. 140. NIH. New NIH-funded memory drug moves into Phase 1 clinical study. 2015. http://www. nih.gov/news-events/news-releases/new-nih-funded-memory-drug-moves-into-phase-1-clinicalstudy. 141. Sun MK, Hongpaisan J, Lim CS, Alkon DL. Bryostatin-1 restores hippocampal synapses and spatial learning and memory in adult fragile x mice. J Pharmacol Exp Ther 2014;349(3):393–401. 142. Pradal J, Zuluaga MF, Maudens P, Waldburger JM, Seemayer CA, Doelker E, Gabay C, Jordan O, Allemann E. Intra-articular bioactivity of a p38 MAPK inhibitor and development of an extendedrelease system. Eur J Pharm Biopharm 2015;93:110–117. Medicinal Research Reviews DOI 10.1002/med


r 1221

143. Alam JJ. Selective brain-targeted antagonism of p38 MAPKalpha reduces hippocampal IL-1beta levels and improves morris water maze performance in aged rats. J Alzheimers Dis 2015;48(1):219– 227. ¨ ¨ 144. Lues I, Weber F, Meyer A, Buhring U, Hoffmann T, Kuhn-Wache K, Manhart S, Heiser U, Pokorny R, Chiesa J, Glund K. A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, aВ glutaminyl cyclase inhibitor, in healthy subjects. Alzheimer’s & Dementia: Translational Research & Clinical Interventions 2015;1(3):182–195. 145. Takamura Y, Ono K, Matsumoto J, Yamada M, Nishijo H. Effects of the neurotrophic agent T817MA on oligomeric amyloid-beta-induced deficits in long-term potentiation in the hippocampal CA1 subfield. Neurobiol Aging 2014;35(3):532–536. 146. Boxer AL, Lang AE, Grossman M, Knopman DS, Miller BL, Schneider LS, Doody RS, Lees A, Golbe LI, Williams DR, Corvol JC, Ludolph A, Burn D, Lorenzl S, Litvan I, Roberson ED, Hoglinger GU, Koestler M, Jack CR Jr., Van Deerlin V, Randolph C, Lobach IV, Heuer HW, Gozes I, Parker L, Whitaker S, Hirman J, Stewart AJ, Gold M, Morimoto BH. Davunetide in patients with progressive supranuclear palsy: A randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet 2014;13(7):676–685. 147. Jouroukhin Y, Ostritsky R, Assaf Y, Pelled G, Giladi E, Gozes I. NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: Protection against impairments in axonal transport. Neurobiol Dis 2013;56:79–94. 148. Medipost. “NEUROSTEM-AD” the treatment for Alzheimer’s disease requested for phase 1.2a clinical trials. 2013. http://www.medi-post.com/2013/06/8254/. R -AD in patients with 149. Medipost. The safety and the efficacy evaluation of NEUROSTEM Alzheimer’s disease (NCT01297218). 2012. https://clinicaltrials.gov/ct2/show/NCT01297218. 150. Anand R, Seiberling M, Kamtchoua T, Pokorny R. Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers. Clin Pharmacokinet 2007;46(4):351–358. 151. FGL-L: Treatment of cognition disorders. Drug Data Rep 2006;28(11):1006 ¨ 152. Eriksdotter-Jonhagen M, Linderoth B, Lind G, Aladellie L, Almkvist O, Andreasen N, Blennow ¨ E, Wahlund LO, Wall A, Wiberg K, Bogdanovic N, Jelic V, Kadir A, Nordberg A, Sundstrom ˚ Almqvist P, Wahlberg L. Encapsulated cell biodelivery of nerve growth M, Winblad B, Seiger A, factor to the basal forebrain in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 2012;33(1):18–28. 153. Jelinek GA, Weiland TJ, Hadgkiss EJ, Marck CH, Pereira N, van der Meer DM. Medication use in a large international sample of people with multiple sclerosis: Associations with quality of life, relapse rate and disability. Neurol Res 2015;37(8):662–673. 154. Lawson DH, Lee S, Zhao F, Tarhini AA, Margolin KA, Ernstoff MS, Atkins MB, Cohen GI, Whiteside TL, Butterfield LH, Kirkwood JM. Randomized, placebo-controlled, phase III trial of yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) versus peptide vaccination versus GM-CSF plus peptide vaccination versus placebo in patients with no evidence of disease after complete surgical resection of locally advanced and/or stage IV melanoma: A trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697). J Clin Oncol 2015;33(34):4066– 4076. 155. Garcia JA, Elson P, Tyler A, Triozzi P, Dreicer R. Sargramostim (GM-CSF) and lenalidomide in castration-resistant prostate cancer (CRPC): Results from a phase I-II clinical trial. Urol Oncol 2014;32(1):33.e11–37. 156. Marsh SE, Abud EM, Lakatos A, Karimzadeh A, Yeung ST, Davtyan H, Fote GM, Lau L, Weinger JG, Lane TE, Inlay MA, Poon WW, Blurton-Jones M. The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc Natl Acad Sci USA 2016;113(9):E1316–1325.


1222


157. McGeer PL, Akiyama H, Itagaki S, McGeer EG. Immune system response in Alzheimer’s disease. Can J Neurol Sci 1989;16(4 Suppl):516–527. 158. Deardorff WJ, Grossberg GT. Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics. Exp rev neurother 2017;17(1):17–32 159. Shin JH, Lee YA, Lee JK, Lee YB, Cho W, Im DS, Lee JH, Yun BS, Springer JE, Gwag BJ. Concurrent blockade of free radical and microsomal prostaglandin E synthase-1-mediated PGE2 production improves safety and efficacy in a mouse model of amyotrophic lateral sclerosis. J Neurochem 2012;122(5):952–961. 160. GliaCure. Safety, tolerability, and pharmacokinetic study of single ascending doses of GC021109 in healthy subjects (NCT02254369). 2014. https://clinicaltrials.gov/ct2/show/NCT02254369. 161. Huang WJ, Zhang X, Chen WW. Role of oxidative stress in Alzheimer’s disease. Biomed Rep 2016;4(5):519–522. 162. Butchart J, Brook L, Hopkins V, Teeling J, Puntener U, Culliford D, Sharples R, Sharif S, McFarlane B, Raybould R, Thomas R, Passmore P, Perry VH, Holmes C. Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology 2015;84(21):2161–2168. 163. Lee DS, Choi J, Kim SH, Kim S. Ameliorating effects of HX106N, a water-soluble botanical formulation, on Abeta25-35-induced memory impairment and oxidative stress in mice. Biol Pharm Bull 2014;37(6):954–960. 164. Shen C, Chen L, Jiang L, Lai TY. Neuroprotective effect of epigallocatechin-3-gallate in a mouse model of chronic glaucoma. Neurosci Lett 2015;600:132–136. 165. SK Chemicals. A confirmatory trial of SK-PC-B70M in mild to moderate Alzheimer’s disease (NCT01249196). 2010. https://clinicaltrials.gov/ct2/show/NCT01249196. 166. Yang G, Wang Y, Sun J, Zhang K, Liu J. Ginkgo biloba for mild cognitive impairment and Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials. Curr Top Med Chem 2016;16(5):520–528. 167. Whanin Pharmaceutical Company. An efficacy and safety study of INM-176 for the treatment of patients with Alzheimer type dementia (NCT01245530). 2010. https://clinicaltrials. gov/ct2/show/NCT01245530. 168. Farias GA, Guzman-Martinez L, Delgado C, Maccioni RB. Nutraceuticals: A novel concept in prevention and treatment of Alzheimer’s disease and related disorders. J Alzheimers Dis 2014;42(2):357– 367. 169. Li F, Gong Q, Dong H, Shi J. Resveratrol, a neuroprotective supplement for Alzheimer’s disease. Curr Pharm Des 2012;18(1):27–33. 170. Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA, Raman R, Aisen PS. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 2015;85(16):1383–1391. 171. Zhai P, Xia CL, Tan JH, Li D, Ou TM, Huang SL, Gu LQ, Huang ZS. Syntheses and evaluation of asymmetric curcumin analogues as potential multifunctional agents for the treatment of Alzheimer’s disease. Curr Alzheimer Res 2015;12(5):403–414. 172. Kume K, Hanyu H, Sakurai H, Takada Y, Onuma T, Iwamoto T. Effects of telmisartan on cognition and regional cerebral blood flow in hypertensive patients with Alzheimer’s disease. Geriatr Gerontol Int 2012;12(2):207–214. 173. Shindo T, Takasaki K, Uchida K, Onimura R, Kubota K, Uchida N, Irie K, Katsurabayashi S, Mishima K, Nishimura R, Fujiwara M, Iwasaki K. Ameliorative effects of telmisartan on the inflammatory response and impaired spatial memory in a rat model of Alzheimer’s disease incorporating additional cerebrovascular disease factors. Biol Pharm Bull 2012;35(12):2141–2147. 174. Accera. AC-1204 26-week long term efficacy response trial with optional open-label ext (NOURISH AD) (NCT01741194). 2012. https://clinicaltrials.gov/ct2/show/NCT01741194. 175. Sun XJ, Zhao L, Zhao N, Pan XL, Fei GQ, Jin LR, Zhong CJ. Benfotiamine prevents increased beta-amyloid production in HEK cells induced by high glucose. Neurosci Bull 2012;28(5):561– 566. Medicinal Research Reviews DOI 10.1002/med


r 1223

176. O’Hare E, Jeggo R, Kim EM, Barbour B, Walczak JS, Palmer P, Lyons T, Page D, Hanna D, Meara JR, Spanswick D, Guo JP, McGeer EG, McGeer PL, Hobson P. Lack of support for bexarotene as a treatment for Alzheimer’s disease. Neuropharmacology 2016;100:124–130. 177. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 2012;335(6075):1503–1506. 178. Fukasawa H, Nakagomi M, Yamagata N, Katsuki H, Kawahara K, Kitaoka K, Miki T, Shudo K. Tamibarotene: A candidate retinoid drug for Alzheimer’s disease. Biol Pharm Bull 2012;35(8):1206– 1212. 179. Ormerod AD, Thind CK, Rice SA, Reid IC, Williams JH, McCaffery PJ. Influence of isotretinoin on hippocampal-based learning in human subjects. Psychopharmacology 2012;221(4):667–674. 180. Lerner AJ, Gustaw-Rothenberg K, Smyth S, Casadesus G. Retinoids for treatment of Alzheimer’s disease. BioFactors 2012;38(2):84–89. 181. Kelley BJ, Glasser S. Cognitive effects of statin medications. CNS Drugs 2014;28(5):411–419. 182. Kurata T, Miyazaki K, Kozuki M, Morimoto N, Ohta Y, Ikeda Y, Abe K. Progressive neurovascular disturbances in the cerebral cortex of Alzheimer’s disease-model mice: Protection by atorvastatin and pitavastatin. Neuroscience 2011;197:358–368. 183. Zhang YY, Fan YC, Wang M, Wang D, Li XH. Atorvastatin attenuates the production of IL-1beta, IL-6, and TNF-alpha in the hippocampus of an amyloid beta1-42-induced rat model of Alzheimer’s disease. Clin Interv Aging 2013;8:103–110. 184. Barone E, Mancuso C, Di Domenico F, Sultana R, Murphy MP, Head E, Butterfield DA. Biliverdin reductase-A: A novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease. J Neurochem 2012;120(1):135–146. 185. Tong XK, Lecrux C, Rosa-Neto P, Hamel E. Age-dependent rescue by simvastatin of Alzheimer’s disease cerebrovascular and memory deficits. J Neurosci 2012;32(14):4705–4715. 186. Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, Aisen PS. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 2011;77(6):556–563. 187. Liang T, Li R, Cheng O. Statins for treating Alzheimer’s Disease: Truly ineffective? Eur Neurol 2015;73(5-6):360-366. 188. Godyn J, Jonczyk J, Panek D, Malawska B. Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol Rep 2016;68(1):127–138. 189. Novak V. Memory aid by intranasal insulin in diabetes (MemAID) (MemAID) (NCT02415556). 2015. https://clinicaltrials.gov/ct2/show/NCT02415556. 190. Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, Callaghan M, Arbuckle M, Behl C, Craft S. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J Alzheimers Dis 2015;44(3):897– 906. 191. Egefjord L, Gejl M, Moller A, Braendgaard H, Gottrup H, Antropova O, Moller N, Poulsen HE, Gjedde A, Brock B, Rungby J. Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer s disease – Protocol for a controlled, randomized double-blinded trial. Danish Med J 2012;59(10):A4519. 192. Bomba M, Ciavardelli D, Silvestri E, Canzoniero LM, Lattanzio R, Chiappini P, Piantelli M, Di Ilio C, Consoli A, Sensi SL. Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals. Cell Death Dis 2012;4: e612. 193. Shah RC, Matthews DC, Andrews RD, Capuano AW, Fleischman DA, VanderLugt JT, Colca JR. An evaluation of MSDC-0160, a prototype mTOT modulating insulin sensitizer, in patients with mild Alzheimer’s disease. Curr Alzheimer Res 2014;11(6):564–573. 194. Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging 2011;32(9):1626–1633. Medicinal Research Reviews DOI 10.1002/med

1224


195. Lupin. A randomized, double-blind, placebo-controlled, parallel group, comparative, multicenter, phase 2 clinical study to evaluate efficacy and safety of two doses of LND101001 monotherapy in patients with mild to moderate Alzheimer’s disease (EudraCT 2013-001851-11). 2014. https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-001851-11/GB/. 196. Yaari R, Hake A. Alzheimer’s disease clinical trials: Past failures and future opportunities. Clin Investig 2015;5(3):297–309. 197. Merck & Co. Efficacy and safety of MK-7622 as adjunct therapy in participants with Alzheimer’s disease (MK-7622-012) (NCT01852110). 2015. https://clinicaltrials.gov/ct2/show/NCT01852110. 198. Garakani A, Murrough JW, Iosifescu DV. Advances in psychopharmacology for anxiety disorders. FOCUS 2014;12(2):152–162. 199. Lavrovsky Y, Ivachtchenko AV, Morozova M, Salimov RM, Kasey V. Preclinical and early clinical studies of AVN-101, a novel balanced molecule for the treatment of Alzheimer’s disease. Alzheimers Dement 2010;6(4):S583. 200. Regenera Pharma. A randomized SAD and MAD study evaluating the safety and tolerability of RPh201 in healthy subjects and in adults with Alzheimer’s disease (NCT01513967). 2012. https://clinicaltrials.gov/ct2/show/NCT01513967. 201. Gutzmann H, Hadler D. Sustained efficacy and safety of idebenone in the treatment of Alzheimer’s disease: Update on a 2-year double-blind multicentre study. J Neural Transm 1998;54:301–310. 202. Bukatina EE, Grigor’eva IV, Sokol’chik EI. The effectiveness of amiridin in senile dementia of the Alzheimer’s type. Neurosci Behav Physiol 1993;23(1):83–89. 203. Qian ZM, Ke Y. Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer’s Disease? Front Aging Neurosci 2014;6:216 204. Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F. New pharmacological strategies for treatment of Alzheimer’s disease: Focus on disease modifying drugs. Br J Clin Pharmacol 2012;73(4):504– 517. 205. Corbett A, Pickett J, Burns A, Corcoran J, Dunnett SB, Edison P, Hagan JJ, Holmes C, Jones E, Katona C, Kearns I, Kehoe P, Mudher A, Passmore A, Shepherd N, Walsh F, Ballard C. Drug repositioning for Alzheimer’s disease. Nat Rev Drug Discov 2012;11(11):833–846. 206. Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B, Kivipelto M. Clinical trials and late-stage drug development for Alzheimer’s disease: An appraisal from 1984 to 2014. J Intern Med 2014;275(3):251–283. 207. Iqbal K, Grundke-Iqbal I. Developing pharmacological therapies for Alzheimer disease. Cell Mol Life Sci 2007;64(17):2234–2244. 208. Pal R, Larsen JP, Moller SG. The Potential of Proteomics in Understanding Neurodegeneration. International review of neurobiology 2015;121:25–58 209. Whalen J. Experimental Alzheimer’s drug fails in clinical trial. The Wall Street Journal 2016 July 27. http://www.wsj.com/articles/experimental-alzheimers-drug-fails-in-clinical-trial-1469652756. 210. American Academy of Neurology. Women’s better verbal memory skills may mask early signs of Alzheimer’s. 2016. https://www.aan.com/PressRoom/Home/PressRelease/1496. 211. Begley S. Alzheimer’s researchers seethe over years of missteps after latest drug failure. 2016. https://www.statnews.com/2016/07/28/alzheimers-drug-failure/. 212. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer’s disease: Clinical trials and drug development. Lancet 2010;9(7):702–716.

Sergey Bachurin, Director of IPAC RAS. Graduated Chemical Faculty of Moscow State University (MSU) in 1975. In 1980 received the Ph.D. degree and in 1993 defended the Doctor of science degree dissertation. In 2003 was elected as a personal Member of Russian Academy of Medicinal Research Reviews DOI 10.1002/med


r 1225

Sciences. From 1981 till the present time works in the Institute of Physiologically Active Compounds Russian Academy of Sciences (IPAC, RAS). Since 1991 is the Head of the Department of Medicinal and Biological Chemistry; and since 2006 the Director of the IPAC RAS. The main line of Dr. S. Bachurin research activity is related to the discovery of novel efficient neuroprotectors and cognition-enhancers for such neurodegenerative disorders as Alzheimer.s disease, ALS, brain ischemia, etc. The disease-modifying approaches for protection against development of neurodegenerative disorders is proposed and verified in his department, in particular: preventing of synucleinopathy in brain, blocking of mitochondria permeabilization, and activation of autophagy. Bachurin was an invited scholar in the University of California, San Francisco, USA (1992) and in Tufts University School of Medicine, Boston, USA (1995). He is the Chairman of Moscow Chemical Society, National representative at the International Union of Pure and Applied Chemistry (Division “Chemistry and Human Health”). The Editorial Board Member of the journals: “Central Nervous System agents in Medicinal Chemistry” (Associate Editor), “Journal of Nanomedicine & Biotherapeutic Discovery”, “Recent Patent Reviews on CNS Drug Discovery”, “Research in Neurology”, “Russian Chemical Reviews”, and “Russian Chemical Bulletin”. He is the author of more than 200 articles in the scientific journals and about 40 patents for novel biologically active compounds. Elena Bovina, is a Research Associate of IPAC RAS. Graduated from the Faculty of Fuel and Organic Compounds of D.I. Mendeleev Institute of Chemical Technology in Moscow in 1981 and received a diploma of engineer in vitamins and antibiotics technology. In 1985 received her Ph.D. degree in Biotechnology. From 1995 till the present time works in the Institute of Physiologically Active Compounds of Russian Academy of Sciences (IPAC RAS). Since 2014 is the Head of the Department of Information Support. The main line of Dr. E. Bovina.s activity is related to the information and bioinformatics research at IPAC RAS. She is a permanent member of the organizing committees for the Russian Chemical Society. The research is focused on the discovery of novel efficient neuroprotectors and cognition-enhancers for neurodegenerative disorders such as Alzheimer.s disease, amyotrophic lateral sclerosis, brain ischemia, etc. She is the author more than 40 research articles and scientific reports. Aleksey Ustyugov, is a Research Associate of IPAC RAS. The scientific career starts off with studies as an international student at Whitworth University (USA). It provided an opportunity to join the Associated Western Universities Fellowship program through Pacific Northwest National Laboratory where in tight collaboration with material scientists it was possible to discover an efficient method for coating silica gel with active chelating groups in the supercritical fluid conditions. After graduation from Whitworth University with Bachelor of Sciences in Biochemistry, he entered a graduate program at Washington State University (USA). During that period, he focused on characterization and function of small heat shock protein Hsp27 in zebrafish embryos. The subsequent training in the Ph.D. program involved a shift of gears from fish to mice and from analysis of a single protein to analysis of different targets, genetic and biochemical parameters. He used mice overexpressing human gamma-synuclein protein specifically in nervous tissues to deliberately facilitate its aggregation. As a result, it was possible to utilize a model of proteinopathy to study new functions of neuroprotective agents and subsequently generate a new line of research at Institute of Physiologically Active Compounds of Russian Academy of Sciences, Russia. Since 2007, he severed different roles starting from the Junior Research Assistant and reaching to Senior Research Scientist with initiation his own research group that focuses on application of genetic models to study molecular pathways of neurodegenerative disorders and discovery of new functions of novel neuroprotective compounds.
