Optimization of metabolic stability as a goal of modern drug design

Metabolism and other pharmacokinetic (PK) studies have always played a crit ical role in helping to optimize the bioavailability and duration of action of new drugs thereby increasing their success rate. With the advent of aut omated combinatorial synthesis, high-throughput pharmacological testing, an d the ability to create extensive databases in the past decade, drug discov ery has undergone an amazing evolution. With the increased throughput of dr ug discovery, metabolism and other PK studies have evolved to keep pace. Of ten called "early ADME" studies, these studies are characterized by paralle l processing and higher throughput than before. This article focuses on a p articular class of early ADME (absorption, distribution mechanism and excre tion) studies known as "metabolic stability" studies. The theoretical basis for metabolic stability and its relationship to the concept of metabolic i ntrinsic clearance is briefly presented. Some key relationships between str ucture and metabolism are summarized. Several case studies from recent medi cinal chemistry literature are reviewed to exemplify how metabolic stabilit y studies influenced drug design and led to improvements in bioavailability and half-life. Finally, future trends in drug metabolism and analytical ch emistry and how they may influence metabolic stability studies are reviewed . (C) 2001 John Wiley & Sons, Inc.