title: 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.
abstract: 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 relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. lin_yan@merck.com
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Pei
authors.initials: P
authors.lastname: Huo
authors.forename: John S
authors.initials: JS
authors.lastname: Debenham
authors.forename: Christina B
authors.initials: CB
authors.lastname: Madsen-Duggan
authors.forename: Julie
authors.initials: J
authors.lastname: Lao
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Chen
authors.forename: Jing Chen
authors.initials: JC
authors.lastname: Xiao
authors.forename: Chun-Pyn
authors.initials: CP
authors.lastname: Shen
authors.forename: D Sloan
authors.initials: DS
authors.lastname: Stribling
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Shearman
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
authors.forename: Nancy
authors.initials: N
authors.lastname: Tsou
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bateman
authors.forename: Vijay B G
authors.initials: VB
authors.lastname: Reddy
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004285:Dogs; D054314:Drug Inverse Agonism; D004435:Eating / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D020719:Glucuronides / Q000378:metabolism; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008968:Molecular Conformation; D011714:Pyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019440:Anti-Obesity Agents; D051638:Ether-A-Go-Go Potassium Channels; D020719:Glucuronides; C550156:N-(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; D011714:Pyrans; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1