Omarigliptin (MK-3102): A Novel Long-Acting DPP-4 Inhibitor for Once-Weekly Treatment of Type 2 Diabetes

Abstract

In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.

This molecule targets at type 2 diabetes - a single crystal study on (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl] tetrahydro-2H-pyran-3-amine (Omarigliptin), C17H20F2N4O3S

“…Experimental, clinical, and epidemiological studies have shown that type 2 diabetes mellitus is a growing epidemic a ecting approximately 220 million people worldwide [1,2]. The six-members ring B is in the typical chair conformation.…”

“…The title compound was prepared by a literature method [1]. 16.5 g (50.4 mmol) of tert-butyl [(2R,3S)-5-oxo-2-(2,5-di uorophenyl)tetrahydro-2H-pyran-3-yl]carbamate, 19.6 g (56.8 mmol) of pyrazole salt (benzenesulfonic acid and 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo [3,4-c]pyrazole) and 250 mL of dimethylacetamide were mixed while stirring.…”

The crystal structure of tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate, C10H15N3O2

“…The title compound is easily available by a known synthetic protocol [5]. In a typical precepitation reaction 0.3 g of the title compound were dissolved in 5 mL methanol.…”

A randomised, double-blind, trial of the safety and efficacy of omarigliptin (a once-weekly DPP-4 inhibitor) in subjects with type 2 diabetes and renal impairment

“…5 Omarigliptin (MK-3102) is a selective, oral DPP-4 inhibitor with a half-life that enables once-weekly dosing that is primarily eliminated by renal excretion. 10 A once-weekly oral antihyperglycaemic agent (AHA) has the potential to provide patients with T2DM an additional option for managing their glycaemic control as part of a patientcentred approach. Omarigliptin has previously been demonstrated to have efficacy comparable to sitagliptin, a marketed daily DPP-4 inhibitor, 11,12 and is approved in Japan.…”