Discovery, Structure−Activity Relationships, Pharmacokinetics, and Efficacy of Glucokinase Activator (2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0
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- 作者：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 L. Spence ; John Tengi ; Mark T. Dvor
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：May 13, 2010
- 年：2010
- 卷：53
- 期：9
- 页码：3618-3625
- 全文大小：886K
- 年卷期：v.53,no.9(May 13, 2010)
- ISSN：1520-4804
文摘
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.