Discovery of cyclic guanidines as potent, orally active, human glucagon receptor antagonists
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- 作者：Christopher ; Sinz ; ; ; christopher_sinz@merck.com ; Jiang ; Chang ; Ashley Rouse ; Lins ; Ed ; Brady ; Mari ; Candelore ; Qing ; Dallas-Yang ; Victor ; Ding ; Guoqiang ; Jiang ; Zhen ; Lin ; Steven ; Mock ; Sajjad ; Qureshi ; Gino ; Salituro ; Richard ; Saperstein ; Jackie ; Shang ; Deborah ; Szalkowski ; Laurie ; Tota ; Stella ; Vincent ; Michael ; Wright ; Shiyao ; Xu ; Xiaodong ; Yang ; Bei ; Zhang ; James ; Tata ; Ronald ; Kim ; Emma ; Parmee
- 关键词：Diabetes ; Glucagon ; Antagonist ; Guanidine
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2011
- 出版时间：1 December 2011
- 年：2011
- 卷：21
- 期：23
- 页码：7131-7136
- 全文大小：492 K
文摘
In the course of the development of an aminobenzimidazole class of human glucagon receptor (hGCGR) antagonists, a novel class of cyclic guanidine hGCGR antagonists was discovered. Rapid N-dealkylation resulted in poor pharmacokinetic profiles for the benchmark compound in this series. A strategy aimed at blocking oxidative dealkylation led to a series of compounds with improved rodent pharmacokinetic profiles. One compound was orally efficacious in a murine glucagon challenge pharmacodynamic model and also significantly lowered glucose levels in a murine diabetes model.