| Literature DB >> 27994747 |
Liangqin Guo1, Dann L Parker1, Yi Zang1, Ramzi F Sweis1, Weiguo Liu1, Edward C Sherer1, Nicole Buist1, Jenna Terebetski1, Terri Kelly1, Randal Bugianesi1, Birgit T Priest1, Karen H Dingley1, Xiaofang Li1, Stan Mitelman1, Gino Salituro1, Maria E Trujillo1, Michele Pachanski1, Melissa Kirkland1, Mary Ann Powles1, George J Eiermann1, Yue Feng1, Jin Shang1, Andrew D Howard1, Feroze Ujjainwalla1, Christopher J Sinz1, John S Debenham1, Scott D Edmondson1, Ravi P Nargund1, William K Hagmann1, Derun Li1.
Abstract
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.Entities:
Keywords: GPR142 agonists; glucose-stimulated insulin secretion (GSIS); solubility; triazole; type 2 diabetes mellitus (T2DM)
Year: 2016 PMID： 27994747 PMCID： PMC5150677 DOI： 10.1021/acsmedchemlett.6b00314
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345