Development of Stereoisomeric Drugs

An Industrial Perspective

Mitchell N. Cayen Schering-Plough Research Institute, Kenilworth, New Jersey

I. INTRODUCTION

In previous chapters, analytical, biological, and other scientific aspects of drug stereochemistry were described. The purpose of this chapter is to discuss pharmaceutical drug development for those drugs containing a stereogenic center, it is currently estimated that it takes approximately 12 yr to bring a new chemical entity (NCE) to regulatory clearance in the United States, at a cost (including discovery and development) averaging $231 million (1). With such a major resource commitment by the pharmaceutical industry to research and development, it is critical that NCEs be subjected to a rational development program to appropriately evaluate their safety and efficacy. The development of drugs with chiral centers presents specific challenges that must be addressed at various stages from discovery through clinical evaluation and finally to market.

II. DRUG DEVELOPMENT PROGRAM

A typical drug development program is outlined in Fig. 1. NCEs with a chiral center are typically synthesized and initially tested for desired pharmacological activity in animal models and/or in vitro screens as a racemic mixture. Should no pharmacological activity be demonstrated, the NCE is no longer considered a viable candidate drug. However, should some activity emerge, the first decision related to the NCE's chirality is required. Subsequent biological tests are usually more specific regarding drug activity and often require more material for evaluation. What should

Procedure

Form of Chlral Drug

Racemate Race mate

Racemate (+ enantiomer?) Racemate andior enantiomer?

Months

Months

Synthesis)

Pharmacology]

Toxicology"!

ind|

Toxicology (animals) J

Safety (man)

Efficacy (man) Years - Phase I

- Phase II • Phase III Metabolism

Racemate

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