Innovations in drug discovery and development, fueled by rapid advances in technology, have led to novel therapeutics for the prevention and treatment of diseases, greatly improving the quality of patients' lives. These innovations have been driven by increasing investments in research and development by pharmaceutical companies, which to some extent have contributed to the upward-spiraling costs of health care, especially prescription medications. The number of new molecular entities (NMEs) receiving Food and Drug Administration (FDA) approval has declined steadily over the years amid concerns over safety and efficacy, with a worrisome nadir of 24 new approvals in 2001. The application of high-throughput screening (HTS) has resulted in bulging drug discovery pipelines full of novel therapeutics with improved receptor binding and efficacy but often without adequate physicochemical or pharmacokinetic properties, resulting in costly failures. Despite these developments, new drug applications and approvals did not increase in the last decade. Consequently, development of line extensions seems to be a logical course of action for pharmaceutical companies in order to protect their revenue pool. Such line extensions can be achieved by designing novel drug delivery systems to deliver the existing drugs on the market. An attractive alternative is a chemical delivery system such as a prodrug or soft drug that changes the drug molecule itself to improve the drug's physicochemical properties and safety/tolerability profile.1

Historically, the term prodrug or proagent was coined by Albert2 in the late 1950s to denote chemical derivatives that could temporarily alter the physicochemical properties of drugs in order to increase their therapeutic utility and reduce associated toxicity. Prodrugs also have been synonymously referred to as latentiated drugs, bioreversible derivatives, and congeners.3-6 However, the term prodrug gained wider acceptance and usually describes compounds that undergo chemical transformation within the body prior to exhibiting pharmacologic activity. Some of the earliest examples of prodrugs are methenamine and aspirin. In the early stages, prodrugs were obtained fortuitously rather than intentionally; an example is prontosil, which was discovered in the 1930s and later identified as a prodrug of the antibiotic sulfanilamide.7

A prodrug strategy can be implemented for existing marketed chemical entities (post hoc design). The prodrug strategy also can be implemented in early discovery (ad hoc design) during lead optimization to address the physicochemical aspects of the NMEs and to improve the chances of success.8

Prodrugs are pharmacologically inactive compounds that result from transient chemical modifications of a biologically active species and are designed to convert to biologically active species in vivo by a predictable mechanism.9 Soft drugs are pharmaceutical agents that are converted to active species in the biological system. However, soft drugs are active isosteric or isoelectric analogues of a lead compound that are metabolized or deactivated in a predictable and controllable fashion after achieving their therapeutic role.10,11 They are usually desired for local activity and administered at or near the site of action. Hence they exhibit pharmacological effect locally and distribute away from the intended site as inactivated metabolites, thus avoiding undesired side effects or toxicities. Therefore, they can be designed to improve the therapeutic index by simplifying the activity/distribution profile, reducing systemic side effects, eliminating drug interactions by avoiding metabolic routes involving saturable enzyme systems, and preventing long-term toxicity owing to accumulation.

Prodrugs and soft drugs can be used strategically to address different problems. Prodrugs and soft drugs are treated by the FDA as new chemical entities, and in most cases they require complete toxicological evaluation prior to submission. The soft-drug approach is gaining acceptance as a way to build a metabolic pathway to a drug in order to achieve predictable metabolism and address the safety and toxicity issues.

This chapter discusses the rationale, design concepts, and application of prodrugs and their current status in drug development and delivery.

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