Design, synthesis and structure activity relationships of indazole and indole derivatives as potent glucagon receptor antagonists. Issue 15 (1st August 2019)

• Record Type: Journal Article
• Authors: Song, Fengbin; Xu, Guozhang; Gaul, Michael D.; Zhao, Baoping; Lu, Tianbao; Zhang, Rui; DesJarlais, Renee L.; DiLoreto, Karen; Huebert, Norman; Shook, Brian; Rentzeperis, Dennis; Santulli, Rosie; Eckardt, Annette; Demarest, Keith
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 15(2019)
• Page Start: 1974
• Page End: 1980
• Publication Date: 2019-08-01
• Subjects: Glucagon -- Glucagon receptor antagonist -- Indazole -- Indole -- Diabetes mellitus; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.05.036
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes.