Application of Bioisosteres in the Design and Discovery of FDA-Approved Drugs and Advanced Clinical Candidates

Since its introduction in 1951, bioisosterism has become a cornerstone strategy in drug design and development, enabling chemists to rationally modify molecular structures to optimize biological and physicochemical properties. In this perspective, we examine 57 FDA-approved drugs and 18 advanced drug candidates wherein bioisosteric replacements were successfully employed to address a range of developability challenges encountered during lead optimization. These strategic substitutions have led to significant improvements in potency, selectivity, solubility, and metabolic stability, while simultaneously mitigating issues related to lipophilicity, plasma protein binding, and the formation of reactive metabolites. Together, these examples highlight the enduring impact of bioisosterism as a versatile tool for fine-tuning drug candidates and overcoming the multifaceted challenges of modern medicinal chemistry.