Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes
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- 作者：Jonathan E. Wilson ; jonathan_wilson@merck.com" class="auth_mail" title="E-mail the corresponding author ; Ravi Kurukulasuriya ; Christopher Sinz ; Matthew Lombardo ; Kate Bender ; Dann Parker ; Edward C. Sherer ; Melissa Costa ; Karen Dingley ; Xiaofang Li ; Stanley Mitelman ; Sharon Tong ; Randal Bugianesi ; Anka Ehrhardt ; Birgit Priest ; Kevin Ratliff ; Feroze Ujjainwalla ; Ravi Nargund ; William K. Hagmann ; Scott Edmondson
- 关键词：GPR142 ; g-protein coupled receptor 142 ; HTS ; high throughput screen ; PPB ; plasma protein binding ; CYP ; cytochrome P450
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：15 June 2016
- 年：2016
- 卷：26
- 期：12
- 页码：2947-2951
- 全文大小：1888 K
文摘
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.