The Discovery of the Dipeptidyl Peptidase-4 (DPP4) Inhibitor Onglyza™: From Concept to Market

Utilizing modern principles of rational drug design originally pioneered by Miguel Ondetti and David Cushman in the discovery of captopril, the team at Bristol-Myers Squibb discovered saxagliptin (Onglyza™), a small-molecule peptidomimetic inhibitor of dipeptidyl peptidase-4 (DPP4). The unique constellation of features exhibited by this compound (low molecular weight, high DPP4 potency, slow-tight binding kinetics, high enzymatic selectivity, good pharmacokinetics and a superior pharmacodynamic response) enabled its advancement in clinical trials, where it demonstrated a robust efficacy and safety profile in the treatment of type-2 diabetes. As a result, saxagliptin was granted marketing approval in both the US and the EU in 2009. This chapter outlines the discovery efforts and thought principles utilized in the conception, design, and discovery of saxagliptin and its progression to registration as a new, safe and effective drug for the treatment of diabetes.