Discovery, Structure−Activity Relationships, Pharmacokinetics, and Efficacy of Glucokinase Activator (2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675)
Journal of Medicinal Chemistry2010Vol. 53(9), pp. 3618–3625
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Nancy-Ellen Haynes, Wendy L. Corbett, Fred T. Bizzarro, Kevin R. Guertin, Darryl W. Hilliard, George W. Holland, Robert F. Kester, Paige E. Mahaney, Lida Qi, Cheryl Spence, J. P. TENGI, Mark Dvorozniak, Aruna Railkar, Franz M. Matschinsky, Joseph F. Grippo, Joseph Grimsby, Ramakanth Sarabu
Abstract
Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.
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