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NEUROPHARMACOLOGY

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

Departments of Metabolic Disorders (T.M.F., X.-M.G., D.J.M., C.-P.S., J.L., H.Y., Y.F., J.C.X., L.H.T.V.d.P.), Pharmacology (D.S.S., K.M.R., A.M.S., D.E.M., L.P.S.), and Medicinal Chemistry (M.T.G., W.K.H., L.S.L., T.J.L., J.P.J., P.L., S.K.S., H.Q., X.T., J.W., S.S.X.), Merck Research Laboratories, Rahway, New Jersey; and Department of Imaging Research, Merck Research Laboratories, West Point, Pennsylvania (B.F.)

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.

Address correspondence to: Dr. Tung M. Fong, Merck Research Laboratories, R80M-213, P.O. Box 2000, Rahway, NJ 07065. E-mail: tung_fong{at}merck.com

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