Sitagliptin phosphate (JANUVIA�) is the first DPP-4 inhibitor approved by the US FDA for the treatment of patients with Type 2 diabetes. The objective of the 2nd generation DPP-4 program is to identify a long acting DPP-4 inhibitor for a once weekly dosing. Based on X-ray crystallography of sitagliptin bound to DPP-4, we proposed that a cyclohexylamine group could be an appropriate replacement for the central �-amino butanoyl portions of sitagliptin, providing a ring constrained analog such as 1  . Compound 1  which has three chiral centers proved to be a potent, selective DPP-4 inhibitor with excellent pharmacokinetic profile in preclinical species. Further modification of 1  and continued effort in this area provided Omarigliptin (MK-3102)  as a clinical candidate, that is currently in Phase 3 clinical studies. In this presentation, the discovery of MK-3102  and its biological profile including efficacy in reducing glucose will be discussed.

Design of chiral DPPIV inhibitors

247th National Meeting (2014)

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