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.
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.
Lin
Linus S
LS
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com
Lanza
Thomas J
TJ
Jewell
James P
JP
Liu
Ping
P
Shah
Shrenik K
SK
Qi
Hongbo
H
Tong
Xinchun
X
Wang
Junying
J
Xu
Suoyu S
SS
Fong
Tung M
TM
Shen
Chun-Pyn
CP
Lao
Julie
J
Xiao
Jing Chen
JC
Shearman
Lauren P
LP
Stribling
D Sloan
DS
Rosko
Kimberly
K
Strack
Alison
A
Marsh
Donald J
DJ
Feng
Yue
Y
Kumar
Sanjeev
S
Samuel
Koppara
K
Yin
Wenji
W
Van der Ploeg
Lex H T
LH
Goulet
Mark T
MT
Hagmann
William K
WK
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
D019440:Anti-Obesity Agents; D002186:Cannabinoids; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000242:Cyclic AMP