作者
Ramakanth Sarabu,Fred Thomas Bizzarro,Wendy Lea Corbett,Mark T. Dvorozniak,Wanping Geng,Joseph F. Grippo,Nancy-Ellen Haynes,Stanley D. Hutchings,Lisa M. Garofalo,Kevin Richard Guertin,Darryl W. Hilliard,Marek M. Kabat,Robert Francis Kester,Wang Ka,Zhenmin Liang,Paige Erin Mahaney,Linda Marcus,Franz M. Matschinsky,David J Moore,Jagdish Kumar Racha,Roumen Nikolaev Radinov,Yi Ren,Lida Qi,Michael Pignatello,Cheryl Spence,Thomas G. Steele,John Tengi,Joseph Grimsby
摘要
Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.