| Literature DB >> 27240550 |
Jonathan E Wilson1, Ravi Kurukulasuriya2, Christopher Sinz2, Matthew Lombardo2, Kate Bender2, Dann Parker2, Edward C Sherer2, Melissa Costa2, Karen Dingley2, Xiaofang Li2, Stanley Mitelman2, Sharon Tong2, Randal Bugianesi2, Anka Ehrhardt2, Birgit Priest2, Kevin Ratliff2, Feroze Ujjainwalla2, Ravi Nargund2, William K Hagmann2, Scott Edmondson2.
Abstract
A novel series of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists are described. The series was designed to address the suboptimal PK (pharmacokinetic) and off-target profile of a class of N-aryl-benzo-[1,4]-oxazepine-4-carboxamides, represented by 1, that were identified from a high-throughput screen of the Merck compound collection for GPR142 agonists. This work led to the discovery of 3-phenoxy-benzo-[1,2,4]-triazolo-[1,4]-oxazepine 47, a potent GPR142 agonist with an off-target and PK profile suitable for in vivo studies. This compound and a related analogue 40 were shown to be active in mouse oral glucose tolerance tests (OGTTs). Furthermore, a GPR142 knock-out mouse OGTT study with compound 40 provides evidence that its glucose-lowering effect is mediated by GPR142.Entities:
Keywords: Diabetes; GPR142; Wild-type knock-out study
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Year: 2016 PMID： 27240550 DOI： 10.1016/j.bmcl.2016.04.018
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823