Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the Treatment of Type 2 Diabetes
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- 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 <b>4b> 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 <b>20eb>, 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 <b>20eb> is GPR142-mediated, and GPR142 agonists could be used as a potential treatment for type 2 diabetes.