Introduction

Although it is well recognized that a clinically useful drug must possess balanced characteristics in terms of efficacy and safety as well as drugability, traditional drug discovery and design efforts have not focused sufficiently on the latter. Consequently, challenges concerning oral bioavailability, pharmacokinetics, and pharmaceutical technical properties have only been dealt with during the development phase, which in many cases has proven to be difficult.

The inappropriateness of this old paradigm to drug design has become evident to the pharmaceutical industry. The implementation of high-throughput screening and combinatorial chemistry have led to the identification of numerous lead compounds with excellent pharmacological properties in terms of affinity and specificity but at the same time inadequate pharmaceutical, biopharmaceutical, and absorption, distribution, metabolism, and excretion (ADME) properties such as low aqueous solubility or high metabolic liability, thus resulting in a significant increase in the development time and the cost or even the closure of projects.

Old paradigm Drug discovery Drug development

New paradigm Drug discovery and early development

Old paradigm Drug discovery Drug development

New paradigm Drug discovery and early development

FIGURE 9.1 Shift in drug discovery/drug development paradigm.

In the new paradigm, an integrated approach to drug design is introduced that takes into account optimization of lead compounds based upon both pharmacological (affinity and specificity), ADME (clearance, metabolic enzymes, and protein binding) and biopharmaceutical (lipophilicity, cell membrane permeability), as well as pharmaceutical (solubility, physical and chemical stability) properties. This is illustrated in Figure 9.1.

However, with the integrated approach it may still prove to be a Herculean task to compress all the desired characteristics of efficacy, safety, and drugability into a single molecule. One potential solution to this challenge is the utilization of the prodrug principle as part of drug design and discovery.

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