The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.

Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.

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Enzymes offer unique opportunities for drug design that are not available to cell surface receptors, nuclear hormone receptors, ion channels, transporters, and DNA. Here, we review the variety of inhibition mechanisms for enzyme-targeted drugs, and establish an enzyme target database for drugs currently marketed in the United States. From an analysis of the FDA Orange Book, there are 317 marketed drugs that work by inhibiting an enzyme. These drugs inhibit 71 enzymes, including 48 human, 13 bacterial, five viral, four fungal, and one protozoal enzyme. Among the 317 drugs, 65% either undergo reactive chemistry in the active site of the target enzyme or contain a structural motif related to the substrate. Among the 71 enzyme targets, 25 are irreversibly inhibited by drugs, and 19 of the 25 irreversibly inhibited enzymes are covalently modified by the drug. In two additional cases, the drug forms a covalent complex with the substrate, and in three more cases, the drug traps a covalent enzyme-substrate intermediate. Four of the 71 enzymes are inhibited by transition-state analogues. Moreover, advanced methods for determining transition-state structure now offer the opportunity for direct drug design without resorting to expensive random testing campaigns. A full appreciation of enzyme mechanisms sets enzymes apart as a specialized class of targets for highly directed drug design.

No abstract