Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes

• Published in: Bioorganic & medicinal chemistry letters 2016-06, Vol.26 (12), p.2947-2951
• Main Authors: Wilson, Jonathan E., Kurukulasuriya, Ravi, Sinz, Christopher, Lombardo, Matthew, Bender, Kate, Parker, Dann, Sherer, Edward C., Costa, Melissa, Dingley, Karen, Li, Xiaofang, Mitelman, Stanley, Tong, Sharon, Bugianesi, Randal, Ehrhardt, Anka, Priest, Birgit, Ratliff, Kevin, Ujjainwalla, Feroze, Nargund, Ravi, Hagmann, William K., Edmondson, Scott
• Format: Article
• Language: English
• Subjects: Animals; Diabetes; Diabetes Mellitus, Experimental - drug therapy; Dose-Response Relationship, Drug; Drug Discovery; Glucose Tolerance Test; GPR142; Mice; Mice, Knockout; Molecular Structure; Oxazepines - chemical synthesis; Oxazepines - chemistry; Oxazepines - pharmacology; Rats; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - deficiency; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Wild-type knock-out study
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.04.018

[Display omitted] 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.