Phenyl rings are ubiquitous in drug design and the most prevalent ring in marketed drugs. Many quantitative structure-activity relationship analyses have focused on the effect of phenyl substituents and the Topliss tree approach provides a road map toward optimization of substitution patterns. However the planarity and lipophilicity of phenyl rings can lead to suboptimal physicochemical properties while metabolic modification in vivo can lead to the generation of reactive metabolites that may bind covalently to proteins. The last decade has seen the design and implementation of a range of phenyl ring isosteres that provide effective mimicry of ortho-, meta- and para-substituted topologies while offering improved physicochemical properties and developability advantages. This presentation will provide a synopsis of recent applications of phenyl and biphenyl isosteres in drug design.

Phenyl and biphenyl bioisosteres: The whys and wherefores of their design and application

ACS Fall 2021

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