Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), in rodents.
The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding K(i) of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma C(max) of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30-40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.
Fong
Tung M
TM
Department of Metabolic Disorders, Merck Research Laboratories, R80M-213, P.O. Box 2000, Rahway, NJ 07065, USA. tung_fong@merck.com
Guan
Xiao-Ming
XM
Marsh
Donald J
DJ
Shen
Chun-Pyn
CP
Stribling
D Sloan
DS
Rosko
Kim M
KM
Lao
Julie
J
Yu
Hong
H
Feng
Yue
Y
Xiao
Jing C
JC
Van der Ploeg
Lex H T
LH
Goulet
Mark T
MT
Hagmann
Williams K
WK
Lin
Linus S
LS
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
Francis
Barbara
B
Strack
Alison M
AM
MacIntyre
D Euan
DE
Shearman
Lauren P
LP
D000577:Amides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D003511:Cyclohexanols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010880:Piperidines / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014162:Transfection
C505559:2-iodophenyl-(1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl)methanone; D000577:Amides; D019440:Anti-Obesity Agents; D003511:Cyclohexanols; D007211:Indoles; D010880:Piperidines; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D005576:Colforsin; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000242:Cyclic AMP; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide