Discovery of N-Aryl-2-acylindole human glucagon receptor antagonists
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- 作者：Christopher ; Sinz ; ; ; christopher_sinz@merck.com ; Amy ; Bittner ; Ed ; Brady ; Mari ; Candelore ; Qing ; Dallas-Yang ; Victor ; Ding ; Guoqiang ; Jiang ; Zhen ; Lin ; 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 R. ; Parmee
- 关键词：Glucagon ; Diabetes ; Glucose ; Antagonist ; Indole
- 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：7124-7130
- 全文大小：730 K
文摘
A novel class of N-aryl-2-acylindole human glucagon receptor (hGCGR) antagonists is reported. These compounds demonstrate good pharmacokinetic profiles in multiple preclinical species. One compound from this series, indole 33, is orally active in a transgenic murine pharmacodynamic model. Furthermore, a 1 mg/kg oral dose of indole 33 lowers ambient glucose levels in an ob/ob/hGCGR transgenic murine diabetes model. This compound was deemed suitable for preclinical safety studies and was found to be well tolerated in an 8-day experimental rodent tolerability study. The combination of preclinical efficacy and safety observed with compound 33 highlights the potential of this class as a treatment for type 2 diabetes.