Discovery of N-[(4R)-6-(4-Chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596) as a Novel Cannabinoid-1 Receptor (CB1R) Inverse Agonist for the Treatment of Obesity

• Published in: Journal of medicinal chemistry Vol. 53; no. 10; pp. 4028 - 4037
• Main Authors: Yan, Lin, Huo, Pei, Debenham, John S, Madsen-Duggan, Christina B, Lao, Julie, Chen, Richard Z, Xiao, Jing Chen, Shen, Chun-Pyn, Stribling, D. Sloan, Shearman, Lauren P, Strack, Alison M, Tsou, Nancy, Ball, Richard G, Wang, Junying, Tong, Xinchun, Bateman, Thomas J, Reddy, Vijay B. G, Fong, Tung M, Hale, Jeffrey J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27.05.2010
• Subjects: Animals; Anti-Obesity Agents - chemical synthesis; Anti-Obesity Agents - pharmacokinetics; Anti-Obesity Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Binding, Competitive; Body Weight - drug effects; Cell Line; Cricetinae; Cricetulus; Crystallography, X-Ray; Dogs; Drug Inverse Agonism; Eating - drug effects; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Glucuronides - metabolism; Haplorhini; Hepatocytes - metabolism; Humans; Mice; Mice, Knockout; Models, Molecular; Molecular Conformation; Pyrans - chemical synthesis; Pyrans - pharmacokinetics; Pyrans - pharmacology; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - genetics; Stereoisomerism; Structure-Activity Relationship

This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure−activity r...