Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients.
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| Abstract |
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.
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| Authors | Ramakanth Sarabu, Fred T Bizzarro, Wendy L Corbett, Mark T Dvorozniak, Wanping Geng, Joseph F Grippo, Nancy-Ellen Haynes, Stanley Hutchings, Lisa Garofalo, Kevin R Guertin, Darryl W Hilliard, Marek Kabat, Robert F Kester, Wang Ka, Zhenmin Liang, Paige E Mahaney, Linda Marcus, Franz M Matschinsky, David Moore, Jagdish Racha, Roumen Radinov, Yi Ren, Lida Qi, Michael Pignatello, Cheryl L Spence, Thomas Steele, John Tengi, Joseph Grimsby |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 16 Pg. 7021-36 (Aug 23 2012) ISSN: 1520-4804 [Electronic] United States |
| PMID | 22809456 (Publication Type: Journal Article) |
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