Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394

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• 作者：Paul J. Dransfield ; Vatee Pattaropong ; Sujen Lai ; Zice Fu ; Todd J. Kohn ; Xiaohui Du ; Alan Cheng ; Yumei Xiong ; Renee Komorowski ; Lixia Jin ; Marion Conn ; Eric Tien ; Walter E. DeWolf Jr. ; Ronald J. Hinklin ; Thomas D. Aicher ; Christopher F. Kraser ; Steven A. Boyd ; Walter C. Voegtli ; Kevin R. Condroski ; Murielle Veniant-Ellison ; Julio C. Medina ; Jonathan Houze ; Peter Coward
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：7
• 期：7
• 页码：714-718
• 全文大小：401K
• 年卷期：0
• ISSN：1948-5875

文摘

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure–activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC₅₀ of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.