Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1372168 | Bioorganic & Medicinal Chemistry Letters | 2011 | 6 Pages |
Abstract
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.
Graphical abstracthGCGR cAMP IC50 = 14 nM. Active at 1 mpk in an ob/ob/hGCGR murine diabetes model.Figure optionsDownload full-size imageDownload as PowerPoint slide
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Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Christopher Sinz, 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,