Bioisosteric modifications

Stewart DJ, Fahmy H, Roth BL et al (2006) Bioisosteric modification of salvinorin A, a potent and selective kappa-opioid receptor agonist. Arzneim Forsch 56 269-275... 

Valgeirsson, J., Nielsen, E. O., Peters, D., Mathiesen, C., Kristensen, A. S., Madsen, U. Bioisosteric modifications of 2-arylureidobenzoic acids selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5. J. Med. Chem. 2004, 47(27), 6948-6957. 

The discovery and development of a candidate for clinical evaluation is a long process that involves small modifications to a lead compound to improve some of its properties, such as pharmacological activity, selectivity, and pharmacokinetics. This is often achieved by the medicinal chemists by replacing a functional group with groups sharing similar physical or chemical properties and maintaining similar activity, which are defined as bioisosteres. We will hereby provide a historical overview of the development and evolution of the concepts of isosterism and bioisosterism, followed by a selection of successful examples of bioisosteric modifications reported in the literature. 

To address the limitation of substrate specificity leading to narrow range applicability—soil enrichment and bioisosteric modifications have been developed to broaden the range of substrates which could be catalyzed by an enzyme. 

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