Prodrugs-Current and Future Drug Development ...

International Journal of Medical and Pharmaceutical Case Reports

1(2): 58-63, 2014; Article no. IJMPCR.2014.009 SCIENCEDOMAIN international www.sciencedomain.org

Prodrugs-Current and Future Drug Development Strategy Rafik Karaman1,2* 1

Department of Pharmaceutical Sciences, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Palestine. 2 Department of Science, University of Basilicata, Potenza, Italy. Author’s contribution The sole author designed, analyzed and interpreted and prepared the manuscript.

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Editorial

Received 8 May 2014 th Accepted 13 August 2014 th Published 26 August 2014

ABSTRACT The focus of traditional prodrug approach was on altering various physiochemical parameters, whereas the current modern computational approach considers designing prodrugs through attaching appropriate linkers with drugs having poor bioavailability which upon exposure to physiological environments release the parent active drugs in a programmable (controlled) manner resulting in an improvement of their bioavailability. With the possibility of designing prodrugs with different linkers, the release rate of the parent active drugs can be controlled. The future of prodrug technology is exciting and yet challenging. Advances must be made in understanding the chemistry of many organic reactions that can be effectively utilized to enable the development of more types of prodrugs. The understanding of organic reaction mechanisms of certain processes, particularly intramolecular reactions, will be the next major milestone in this field. It is envisioned that the future of prodrug technology holds the ability to create safe and efficacious delivery of a wide range of active small molecules and biotherapeutics. This goal can be achieved using computational chemistry methods such as ab initio, semi-empirical and density functional theory (DFT), and molecular mechanics (MM) to calculate physicochemical and molecular properties of current marketed drugs suffer low bioavailability or/and unpleasant taste or odor.

____________________________________________________________________________________________ *Corresponding author: E-mail: [email protected];

Karaman; IJMPCR, Article no. IJMPCR.2014.009

Keywords: Prodrugs; intramolecular processes; DFT; ab initio; targeted physicochemical properties; ADME; computational chemistry.

prodrugs;

Over the past four decades, the pharmaceutical industry has experienced a swift shift towards drug discovery and development. The pharmaceutical research has been subjected to significant alterations in terms of improving or eliminating drug drawbacks related to physicochemical properties which determine the pharmacokinetic behavior (absorption, distribution, excretion, and metabolism (ADME)), pharmaceutical and biological performance of already existing drugs which may pose obstacles to drug development process. To overcome the undesirable physicochemical, biological and organoleptic properties of some marketed drugs, development of new chemical compounds with satisfactory efficacy and safety has to be made. However, this is very expensive and time consuming process [1-11]. Drug discovery is considered as a lengthy interdisciplinary endeavor. It is a multi step and consecutive approach that starts with a certain target and lead compound, followed by optimization and in vitro and in vivo studies to determine if a lead compound fulfills a number of criteria in order to start clinical development [12,13]. It is estimated that about 10-15 years it takes to introduce a new drug to the pharmaceutical market with a cost of exceeding $1 billion dollars. In the past, drugs discovery was a time-consuming process which involves multi-step synthesis followed by in vivo biological screening and investigation of the absorption, distribution, metabolism, excretion (ADME) properties, and potential toxicity of the promising drug candidate. This lengthy process has led to high attrition rates with many failures stemmed from poor pharmacokinetic properties, lack of efficacy, toxicity and side effects [12,13]. At present, revolutionary steps in drug discovery and development process have been established due to the advent of genomics, proteomics, bioinformatics, combinatorial chemistry, high throughput screening, virtual screening, de novo design, in vitro, in silico ADME screening, and structure-based drug design [14,15]. Various computational methods are utilized for the design of high-affinity receptor or enzyme binders either through virtual computer screening of compound libraries or through design and synthesis of novel entities. These computational methods also evaluate the target structures for possible binding to active sites, generate candidate chemical structures, assign their drug-likeness properties, dock chemical structures with the desired target’s active site, and optimize the candidate molecules for improve their binding properties. However, these computational methods along with the techniques used for developing a drug candidate can provide good in vitro drug activity but this cannot be extrapolated to good in vivo drug activity unless a drug candidate has good bioavailability and a desirable duration of action (good clinical profile). Therefore, a growing awareness of finding alternative approaches as determinants of in vivo drug therapeutic activity has led the drug industry to pursue the prodrug approach as a prime priority. The rationale of using prodrugs is to achieve optimum ADME properties and to greatly enhance the selectivity of a drug for its target’s active site. Utilizing the prodrug approach has the potential to provide drugs with improved properties and may also represent a life cycle management opportunity. Hence, it becomes much more feasible, cheaper and less time-consuming to modify and improve the physicochemical properties of already existing drugs through utilizing the 59


prodrug approach [5]. A consensus has been reached that the prodrug approach is a promising and well established strategy to develop new entities with superior efficacy, selectivity and reduced toxicity. Therefore, an optimized therapeutic outcome can be accomplished [1-11]. Approximately, tenth of all worldwide marketed medicines can be classified as prodrugs, and in 2008 alone, a third of all approved drugs with low molecular weight were prodrugs. This fact without any doubt indicates the great success of the prodrug approach [1-11]. Traditionally, the prodrug approach was aimed to improve physicochemical properties of drugs such as solubility and permeability via covalently attaching the drug moiety to a nontoxic chemical promoiety. The prodrug moiety is intended to interconvert within the body non-specifically or specifically by specific enzymes to give rise to the parent active drug. The prodrug can be hydrophilic aiming to increase solubility in gastro-intestinal tract (GIT) or lipophilic aiming to enhance membrane permeability. Such prodrugs suffer from non-specific activation at sites other than the active site resulting in related toxicities and low bioavailability. The molecular revolution and the advance in computational chemistry in recent years, and the ample increase in knowledge of the structure and functions of enzymes and transporters have created a new era of prodrugs which are termed ‘targeted prodrugs’. Researchers have now shifted from their way in synthesizing classical prodrugs into designing prodrugs for specific targeting of enzymes and transporters, thus increasing bioavailability and reducing toxicity, and thus achieving a better therapeutic drug’s profile [1-11]. Targeted prodrugs can be divided into two kinds of approaches: the first by which a chemical moiety is linked to the parent active drug to selectively target an activating enzyme and the second by which the prodrug moiety is interconverted by intramolecular process to give the corresponding parent drug and a non-toxic linker without an involvement of enzymes [5-7]. Targeting using enzymes and transporters requires a great knowledge of the molecular structure and functionalities of those enzymes and transporters. When making a prodrug to target a specific site in the human body, the prodrug must possess a chemical moiety that is specifically recognized by the aimed enzyme or transporter which is usually present exclusively or overexpressed at the desired site of action [2-4]. On the other hand, in the targeted prodrugs that aim to be cleaved without an activation of enzyme the prodrug chemical moiety should be sensitive to the physiological environment by which it is intended to be released such that a desired release rate with a satisfactory duration of action is achieved. The striking efficiency of enzyme catalysis has inspired many organic chemists to explore enzyme mechanism(s) by studying certain intramolecular processes (enzyme models) which proceed faster than their intermolecular counterparts. We have explored these intramolecular processes for utilizing them as linkers for prodrugs of common used drugs. Using computational methods such as DFT, molecular mechanics and abinitio we have assigned the factors affecting the rate-limiting step and determining the mode and action of the intramolecular reaction. Among these intramolecular reactions (enzyme models) are: (i) proton transfer between two oxygen atoms and proton transfer between nitrogen and oxygen in Kirby’s enzyme model; (ii) intramolecular acid-catalyzed hydrolysis in some of Kirby’s maleamic acids; (iii) proton transfer between two oxygen atoms in Menger’s rigid system; (iv) acid-catalyzed lactonization of hydroxy-acids as studied by Cohen and (v) SN2-based cyclization as studied by Bruice.

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The above mentioned computational studies on intramolecularity have demonstrated that there is a necessity to further explore the mechanisms for the intramolecular processes to be utilized in the design for potentially efficient prodrugs. Unraveling the reaction mechanism would allow for an accurate design of an efficient chemical device to be used as a prodrug linker that can be covalently linked to a drug which can chemically, and not enzymatically be cleaved to release the active parent drug in a controlled manner [16-31]. For instance, exploring the mechanism for a proton transfer in Kirby’s acetals has led to a design and synthesis of novel prodrugs of aza-nucleosides to treat myelodysplastic syndromes and statins to treat high cholesterol levels in the blood [32-33]. In the above mentioned examples, the prodrug moiety was attached to the hydroxyl group of the active drug such that the drug promoiety (prodrug) has the potential to degrade upon exposure to physiological environment such as stomach, intestine, and/or blood circulation, with rates that are solely dependent on the structural features of the pharmacologically inactive promoiety (Kirby’s enzyme model). Other linkers such as Kirby’s N-alkylmaleamic acids were also investigated for the design of tranexamic acid prodrugs to treat bleeding conditions [34], acyclovir prodrugs to treat Herpes Simplex [35] and atenolol to treat high blood pressure [23, 36]. Menger’s Kemp acid enzyme model was also utilized for the design of dopamine prodrugs for the treatment of Parkinson’s disease [37]. Prodrugs for dimethyl fumarate to treat psoriasis were designed and synthesized and are currently under in vitro and in vivo kinetic studies [38]. The same approach was utilized for masking the bitter taste of antibacterial drugs such as cefuroxime, amoxicillin and cephalexin and the pain killer, paracetamol [39,40]. The role of the promoiety in the antibacterial and paracetamol prodrugs is to block the free amine in the former case and the phenolic group in the latter which are believed to be responsible for the drug’s bitter sensation. The only difference between the proposed prodrugs and their parent drugs is that the amine or the phenol group in the parent drug is replaced with an amide or ester moiety. Blocking the amine or the hydroxyl group eliminates the capability of the drug moiety to interact with the bitter taste receptor, thus, eliminating the drug’s bitter sensation. In the past, the prodrug approach was viewed as a last resort after all other ways were exploited. Today, the prodrug approach is being considered in the very early stages of the drug discovery and development process. While the traditional prodrug approach was focused on altering various physiochemical parameters, the modern computational approach considers using a design of targeted prodrugs to certain enzymes or transporters or being intraconverted to their parent drugs without metabolic activation process. With the possibility of designing prodrugs with different linkers, the rate of release of the parent drug will be controlled and the drug’s moiety responsible for a bitter sensation will be blocked.

COMPETING INTERESTS Author has declared that no competing interests exist.

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