Prodrug Design

Perspectives, Approaches and Applications in Medicinal Chemistry

Vivekkumar K Redasani, Sanjay B. Bari

• Publisher: Academic Press
• Year: 2015
• Print ISBN:
  9780128035191
• eBook ISBN:
  9780128035573
• Topic: Physical Sciences
• Subtopic: Pharmacology

Prodrug Design: Perspectives, Approaches and Applications in Medicinal Chemistry provides a focused overview of this critical area of drug discovery, as that continuous process strives not only to discover new drug compounds but also to modify the existing ones. This valuable primer supports this mission of drug development and its goal of reducing undesired effects and improving therapeutic effectiveness of drug compounds. Providing a unique compilation of data, insightful case studies, and review of existing literature in the area, the book will promote innovation in medicinal and pharmaceutical chemistry research, exploring the limitations of existing drugs and their improvement. Prodrug Design reviews marketed compounds, the safety of promoieties, and a detailed classification of prodrugs organized by therapeutic area for easy reference. - Offers unique, detailed overview of Prodrug research and literature - Provides detailed chemical structures - Includes Prodrug listing by therapeutic area

Chapter 1

Introduction

Drug design and development aim to achieve a good correlation between structure and activity. They target increased selectivity and specificity associated with drug action. However, unacceptable physicochemical properties limit drug use. Instead of searching for new drugs, it has always been a better approach to correct the limitations linked with existing drugs. The prodrug concept has opened an innovative area for researchers and serves as a “magic bullet” in the drug development process. This concept has set a lifeline for the drugs whose use is restricted due to unwanted side effects. Thus, prodrug design comprises an area of research devoted to optimizing drug delivery.

Keywords

Drug design; biological activity; prodrug; physicochemical properties; high-throughput screening

1.1 Background

The goal of drug design is to correlate biological activity and physicochemical properties. However, drug design should not merely be aimed at increased pharmacological activity. Instead, it is more desirable to achieve a better ratio between the activity and toxicity of drugs. The majority of drugs in use today have been developed by a traditional empirical approach where several thousands of substances have been screened for biological activity and of these only one may eventually become a new drug (Hansch et al., 2005).

1.2 Drug Development

The process of taking a new drug from concept to clinic and eventually to commercialization involves several steps that traditionally occur in series. The discovery and development of a new drug start from the identification and validation of the target protein or receptor. The drug development practice from the target identification to the final product is a time- and money-consuming process (DiMasi et al., 2003). The average cost of taking a compound from the discovery stage to commercialization is estimated to exceed US$800 million, with an average development timespan of ~15 years. Finally, perhaps only one of 10 clinically studied drug candidates may reach the market and, as a whole, the probability for each synthesized compound reaching the market is thus only one in a million. The reasons for this poor percentage of success in the drug development process are poor drug properties, such as solubility and permeability which are amongst the main causes for failure, along with toxicity as an additional factor (Borchardt et al., 2006).

Given these frightening statistics, pharmaceutical companies are under constant pressure to streamline the drug development process. The recent craze of drug patent expirations and subsequent generic competition for blockbuster drugs has further aggravated the need for efficient strategies to screen, identify, and optimize lead compounds for development.

High-throughput screening (HTS) and combinatorial chemistry methodologies have been developed in the past two decades, to synthesize a vast number of compounds using limited resources. Large numbers of molecules are emerging as a result of these methodologies. Several complementary in silico and in vitro strategies have also emerged to screen these compounds and assess their potential to become lead candidates. Compounds emerging as “hits” from these screening processes are characterized further and tested in vivo for safety and efficacy. This phase of preclinical drug development requires that the compound be formulated into a dosage form that can be used to administer the drug. Although simple conventional formulation technologies are preferred at this stage, such technologies are often not applicable for challenging compounds, such as those exhibiting poor aqueous solubility (Chaubal, 2004). However, many such potential drug candidate leads exhibit high affinities towards a variety of molecular targets, such as receptors, enzymes, etc. Not all are going to become real drug candidates due to their inherent physicochemical properties. A drug can only exert a desired pharmacological effect if it reaches its site of action.

Even so, the modern discovery technologies, such as HTS and combinatorial chemistry, can produce novel lead structures with high pharmacological potency, but the physicochemical and biopharmaceutical aspects of the initial leads have frequently been neglected. This can lead to drug candidates with poor drug-like properties that face significant problems later in drug development (Venkatesh and Lipper, 2000).

1.3 The Drug Discovery Process

Drug discovery has evolved from rational drug design, which was slow and time-consuming, to HTS and combinatorial chemistry technologies that can result in up to several compounds being synthesized per chemist per year. Drug discovery productivity has been accelerated further by the availability of information from the genomic database, which provides new biological targets for drug development. Under such circumstances the appropriate screening of a vast number of compounds becomes crucial for the success of the drug discovery program.

Over the past four decades, the pharmaceutical industry has experienced a sharp swing towards discovery and development of new drug molecules. A significant variation is seen in order to improve or eliminate drawbacks related to physicochemical properties which determine the pharmacokinetic behavior, and pharmaceutical and biological performance of already existing drugs.

1.3.1 Goal of Drug Discovery

The goal of many researchers is the design of a drug that hits only the drug target, while minimizing drug exposure to other sites in the body, thus minimizing toxicity. This targeting idea has been the goal of numerous researchers via the use of prodrugs. The frustrations that drug discovery process teams encounter with the new bigger, more complex drug molecule candidates have renewed interest in this novel problem-solving technique and have led to some significant recent commercial successes. To overcome the undesirable physicochemical, biological, and organoleptic properties of some marketed drugs, the development of new chemical compounds with satisfactory efficacy and safety has to be made. However, this is a very expensive and time-consuming process.

1.3.2 Constraints in Drug Discovery

When a new chemical entity has some barrier/limitation to utility, it may not be developed as a therapeutic agent. For example, the drug may be water-soluble, making it difficult for a safe injectable dosage form to be developed for human use. Another limitation might be that the drug, although effective if given by injection, cannot be absorbed through the gastrointestinal tract. This may be because it is very polar to cross the cell linings the gastrointestinal tract or because the chemical is metabolized by enzymes present in these cells or in liver, thus preventing the drug from reaching the systemic circulation.

1.4 Current Scenario in Prodrug Research

At present, revolutionary steps in the drug discovery and development process have been recognized due to the dawn of pharmacogenomics, proteomics, bioinformatics, HTS, virtual screening, de novo design, in silico ADME screening, and structure-based drug design. 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 are very well known in evaluating the target structures for possible binding to active sites, generating candidate chemical structures, assigning their drug-likeness properties, docking chemical structures to active sites and optimizing the candidate molecules to 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 cannot be extrapolated to good in vivo drug activity unless a drug candidate has good bioavailability and a desirable duration of action. 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 pharmacokinetic properties and to enhance greatly the selectivity of a drug for its target’s active site. Utilizing the prodrug approach, the potential drug candidate is made available with improved properties. A harmony has been reached that the prodrug approach is a promising and well-established strategy to develop new entities with superior efficacy and selectivity and reduced toxicity. Therefore, an optimized therapeutic outcome can be accomplished. Approximately a tenth of all worldwide marketed medicines can be classified as prodrugs, and in 2008 alone, a third of all approved drugs with low molecular weights were prodrugs. This fact, without doubt, indicates the great success of the prodrug approach.

Traditionally, the prodrug approach was aimed at improving the physicochemical properties of drugs via covalently attaching the drug moiety to a nontoxic chemical species, the promoiety. The prodrug is intended to interconvert within the body by specific enzymes to liberate the parent active drug. The prodrug can be hydrophilic, aiming to increase solubility in the gastrointestinal tract or aiming to enhance membrane permeability. Such prodrugs suffer from nonspecific 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 structures and functions of enzymes and transporters have created a new era of prodrugs which are termed targeted prodrugs. Researchers have now shifted from synthesizing classical prodrugs to designing prodrugs for specific targeting of enzymes and transporters, thus increasing bioavailability and reducing toxicity, and therefore achieving a better therapeutic profile of drug candidate (Karaman, 2014).

1.5 Need of the Study

According to Professor Takeru Higuchi, “Drugs need to be design with delivery in mind” (quoted in the mid-1970s). This paradigm is very important in terms of drug discovery, and it should be borne in mind at all stages of drug development. Drug metabolism pharmacokinetic research has helped to develop drugs with suitable properties. Novel formulation approaches also help overcome basic delivery limitations caused by problematic physicochemical or biochemical properties. Furthermore, the prodrug approach is an integral approach to drug discovery (Teruko, 2011).

Thus, instead of synthesizing new compounds, which is a time-consuming and too costly affair, the designing of derivatives of existing clinically used drugs is definitely an interesting and promising area of research. Moreover, as the metabolic profile of the liberated parent drug (after cleavage of the derivative in the body) would be already known, it could be advantageous to design prodrug derivatives of parent compounds. Prodrug design comprises an area of research devoted to optimize drug delivery, where the pharmacologically inactive species required transformation within the body in order to release the parent active drug (Halen et al., 2009).

In the past, the prodrug approach was viewed as a last resort after all other ways were exploited, whereas, now-a-days 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 inter-converted to their parent drugs without a 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 (Karaman, 2014).

This growing demand in the drug discovery process encouraged us to produce this particular edition of this book. Great care has been taken to fulfill the needs of students and researchers alike. From the student point of view, the contents will provide precise data and cover mainly the prescribed syllabus of various universities. For the different courses, including basic sciences and pharmaceutical sciences, where there is a need to study the drug discovery process, this book might be a beneficial one. From the research point of view, the examples available enforce one to find a new sight. The realization of the need for and importance of this book promoted us to upgrade the previous edition.

References

1. Borchardt RT, Kerns EH, Hageman MJ, Thakker DR, Stevens JL. Optimizing the “Drug Like” Properties of Leads in Drug Discovery New York, NY: Springer Science and Business Media; 2006.

2. Chaubal MV. Application of formulation technologies in lead candidate selection and optimization. Drug Discov Today. 2004;9(14):603–609.

3. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003;22:15185.

4. Halen PK, Murumkar PR, Giridhar R, Yadav MR. Prodrug designing of NSAIDs. Mini Rev Med Chem. 2009;9(1):124–139.

5. Hansch C, Sammes PG, Taylor JB. Comprehensive Medicinal Chemistry: “Principles of Pharmacokinetics and Metabolism”. vol. 5 Oxford England: Pergamon Press; 2005; pp. 122–133.

6. Karaman R. Prodrugs-current and future drug development strategy. Int J Med Pharm Case Reports. 2014;1(2):58–63.

7. Teruko I. Prodrug approach in current drug discovery. Drug Metab Pharmacokinet. 2011;26(4):307–308.

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Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Preface
• Chapter 1. Introduction
• Chapter 2. Concept of Prodrug
• Chapter 3. Types of Prodrugs
• Chapter 4. Approaches for Prodrugs
• Chapter 5. Applications
• Chapter 6. Role in Drug Discovery
• Chapter 7. Work Reported
• Conclusion