Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes.
Basic Information
ID: ALA4715723
Journal: Bioorg Med Chem Lett
Title: Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes.
Authors: Wilson JE,Kurukulasuriya R,Sinz C,Lombardo M,Bender K,Parker D,Sherer EC,Costa M,Dingley K,Li X,Mitelman S,Tong S,Bugianesi R,Ehrhardt A,Priest B,Ratliff K,Ujjainwalla F,Nargund R,Hagmann WK,Edmondson S
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.
CiteXplore: 27240550
DOI: 10.1016/j.bmcl.2016.04.018
Patent ID: ┄