Potent, orally absorbed glucagon receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters 1999-03, Vol.9 (5), p.641-646
• Main Authors: de Laszlo, Stephen E., Hacker, Candice, Li, Bing, Kim, Dooseop, MacCoss, Malcolm, Mantlo, Nathan, Pivnichny, James V., Colwell, Larry, Koch, Gregory E., Cascieri, Margaret A., Hagmann, William K.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Humans; Medical sciences; Mice; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Receptors, Glucagon - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(99)00081-5

The SAR of 2-pyridyl-3,5-diaryl pyrroles, ligands of the human glucagon receptor and inhibitors of p38 kinase, were investigated. This effort resulted in the identification of 2-(4-pyridyl)-5-(4-chlorophenyl)-3-(5-bromo-2-propyloxyphenyl)pyrrole 49 (L-168,049), a potent (Kb = 25 nM), selective antagonist of glucagon. The SAR of 2-pyridyl-3,5-diaryl pyrroles, antagonists of glucagon and inhibitors of p38 kinase, was investigated, This effort resulted in the identification of 2-(4-pyridyl)-5-(4-chlorophenyl)-3-(5-bromo-2-propyloxyphenyl)pyrrole (L-168,049), a potent (Kb = 25 nM), antagonist of glucagon.