Abstract
Publisher Summary This chapter discusses the use of bioisosteric groups in lead optimization. The concept of bioisosteres refers to compounds or a substructure of compounds that share similar shapes, volumes, electronic distributions, and physiochemical properties, which together produce similar biological activities. It is difficult to clearly define the extent of similarity that is deemed necessary for consideration as a bioisostere. However, despite its ambiguity, medicinal chemists have widely adopted this concept for drug discovery efforts. Bioisosteric replacement is often explored for the lead compound to optimize the potency and selectivity or to improve the overall ADME profile. Sometimes, bioisosteres are used simply to circumvent previous patent coverage of leads in the literature. The chapter covers some of the recent successful bioisosteric replacement work in lead optimization in the literature. It includes some typical, yet unsuccessful, examples of bioisosteric replacements to demonstrate the principles and limitations of this technique. It also discusses the concept of conformational restriction, atom replacement, and heterocyclic ring replacements.
Published Version
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