Discovery of 2-Pyridylureas as Glucokinase Activators
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- 作者：Ronald J. Hinklin ; Thomas D. Aicher ; Deborah A. Anderson ; Brian R. Baer ; Steven A. Boyd ; Kevin R. Condroski ; Walter E. DeWolf ; Jr. ; Christopher F. Kraser ; Maralee McVean ; Susan P. Rhodes ; Hillary L. Sturgis ; Walter C. Voegtli ; Lance Williams ; Jonathan B. Houze
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：October 9, 2014
- 年：2014
- 卷：57
- 期：19
- 页码：8180-8186
- 全文大小：384K
- ISSN：1520-4804
文摘
Glucokinase (GK) is the rate-limiting step for insulin release from the pancreas in response to high levels of glucose. Flux through GK also contributes to reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate GK may address this issue. Herein we report the identification and initial optimization of a novel series of glucokinase activators (GKAs). Optimization led to the identification of 33 as a compound that displayed activity in an oral glucose tolerance test (OGTT) in normal and diabetic mice.