Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the Treatment of Type 2 Diabetes

详细信息    查看全文

• 作者：Liangqin Guo ; Dann L. Parker ; Yi Zang ; Ramzi F. Sweis ; Weiguo Liu ; Edward C. Sherer ; Nicole Buist ; Jenna Terebetski ; Terri Kelly ; Randal Bugianesi ; Birgit T. Priest ; Karen H. Dingley ; Xiaofang Li ; Stan Mitelman ; Gino Salituro ; Maria E. Trujillo ; Michele Pachanski ; Melissa Kirkland ; Mary Ann Powles ; George J. Eiermann ; Yue Feng ; Jin Shang ; Andrew D. Howard ; Feroze Ujjainwalla ; Christopher J. Sinz ; John S. Debenham ; Scott D. Edmondson ; Ravi P. Nargund ; William K. Hagmann ; Derun Li
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：7
• 期：12
• 页码：1107-1111
• 全文大小：385K
• ISSN：1948-5875

文摘

GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound 4 suffered from poor metabolic stability and poor solubility. Lead optimization strategies to improve potency, efficacy, metabolic stability, and solubility are described. This optimization led to compound 20e, which showed significant reduction of glucose excursion in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study. These studies provide strong evidence that reduction of glucose excursion through treatment with 20e is GPR142-mediated, and GPR142 agonists could be used as a potential treatment for type 2 diabetes.