SAR, Pharmacokinetics, Safety, and Efficacy of Glucokinase Activating 2-(4-Sulfonylphenyl)-N-thiazol-2-ylacetamides: Discovery of PSN-GK1

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• 作者：Lisa S. Bertram ; Daniel Black ; Paul H. Briner ; Rosemary Chatfield ; Andrew Cooke ; Matthew C. T. Fyfe ; P. John Murray ; Fré ; dé ; ric Naud ; Masao Nawano ; Martin J. Procter ; Gü ; naj Rakipovski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：July 24, 2008
• 年：2008
• 卷：51
• 期：14
• 页码：4340-4345
• 全文大小：185K
• 年卷期：v.51,no.14(July 24, 2008)
• ISSN：1520-4804

文摘

Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2R)-2-(4-cyclopropanesulfonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.