title: Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity.
abstract: The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lanza
authors.forename: James P
authors.initials: JP
authors.lastname: Jewell
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Shrenik K
authors.initials: SK
authors.lastname: Shah
authors.forename: Hongbo
authors.initials: H
authors.lastname: Qi
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Suoyu S
authors.initials: SS
authors.lastname: Xu
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Chun-Pyn
authors.initials: CP
authors.lastname: Shen
authors.forename: Julie
authors.initials: J
authors.lastname: Lao
authors.forename: Jing Chen
authors.initials: JC
authors.lastname: Xiao
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Shearman
authors.forename: D Sloan
authors.initials: DS
authors.lastname: Stribling
authors.forename: Kimberly
authors.initials: K
authors.lastname: Rosko
authors.forename: Alison
authors.initials: A
authors.lastname: Strack
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.forename: Koppara
authors.initials: K
authors.lastname: Samuel
authors.forename: Wenji
authors.initials: W
authors.lastname: Yin
authors.forename: Lex H T
authors.initials: LH
authors.lastname: Van der Ploeg
authors.forename: Mark T
authors.initials: MT
authors.lastname: Goulet
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002186:Cannabinoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D002186:Cannabinoids; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000242:Cyclic AMP