A Selective Cannabinoid-1 Receptor Antagonist, PF-95453, Reduces Body Weight and Body Fat to a Greater Extent than Pair-Fed Controls in Obese Monkeys Janice D. Wagner, Li Zhang, Kylie Kavanagh, Gina M. Ward, Janice E. Chin, John R. Hadcock, Bruce J. Auerbach, and H. James Harwood, Jr. Department of Pathology, Wake Forest University, Winston-Salem, North Carolina (J.D.W., L.Z., K.K., G.M.W., H.J.H.); and Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer Global Research and Development, Groton, Connecticut (J.E.C., J.R.H., B.J.A., H.J.H.) Received March 14, 2010; accepted July 1, 2010 ABSTRACT Cannabinoid-1 (CB 1 ) receptor antagonists exhibit pharmaco- logical properties favorable to treatment of obesity, caused by both centrally mediated effects on appetite and peripherally mediated effects on energy metabolism. However, the relative contribution of these effects to the weight loss produced by CB 1 receptor antagonists remains unclear. Here, we com- pare food intake-related and independent effects of the CB 1 - selective antagonist 1-(7-(2-chlorophenyl)-8-(4-chlorophe- nyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-(methylamino) azetidine-3-carboxamide (PF-95453) in obese cynomolgus monkeys. Monkeys were divided into three study groups (n = 10 each) and treated once daily for 8 weeks with either vehicle or PF-95453 as follows: 1, fed ad libitum and dosed orally with vehicle; 2, fed ad libitum and dosed orally with PF-95453 (0.5 mg/kg weeks 1–3, 1.0 mg/kg weeks 4 – 8); and 3, fed an amount equal to the amount consumed by the drug-treated group and dosed orally with vehicle (pair-fed). PF-95453 treatment signif- icantly reduced food consumption by 23%, body weight by 10%, body fat by 39%, and leptin by 34% while increasing adiponectin by 78% relative to vehicle-treated controls. Pair- fed animals did not exhibit reductions in body weight or leptin but did show significantly reduced body fat (11%) and in- creased adiponectin (15%) relative to vehicle-treated controls but markedly less than after PF-95453 treatment. Indeed, sig- nificant differences were noted between the drug-treated and pair-fed groups with respect to body weight reduction, body fat reduction, increased adiponectin, and leptin reduction. Similar to humans, monkeys treated with the CB 1 receptor antagonist exhibited decreased body weight and body fat, a substantial portion of which seemed to be independent of the effects on food intake. Introduction The mammalian endocannabinoid system has been exten- sively characterized over the last 20 years and is now known to play a key role in energy homeostasis by modulating both food intake and peripheral energy metabolism (Pagotto et al., 2006; Nogueiras et al., 2008, 2009; Osei-Hyiaman et al., 2008; Cota et al., 2009; Quarta et al., 2010). In general, stimulation of the endocannabinoid system influences meta- bolic pathways that lead to weight gain, lipogenesis, and impaired glycemic control (Hao et al., 2000; Bensaid et al., 2003; Engeli et al., 2005; Jbilo et al., 2005; Poirier et al., 2005; Matias et al., 2006). The endocannabinoid system is composed of transmem- brane endocannabinoid receptors, their endogenous ligands (endocannabinoids), the proteins involved in endocannabi- This work was supported by a grant from Pfizer, Inc. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.110.168187. ABBREVIATIONS: CB 1 , cannabinoid-1 receptor; CB 2 , cannabinoid-2 receptor; PF-95453, 1-(7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-meth- ylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-(methylamino)azetidine-3-carboxamide; GTT, glucose tolerance test; HDLC, high-density lipoprotein choles- terol; CRP, C-reactive protein; MCP-1, monocyte chemoattractant protein 1; ELISA, enzyme-linked immunosorbent assay; DIO, diet-induced obese; AUC, area under the curve; DEXA, dual-energy X-ray absorptiometry; PK, pharmacokinetic; CE-178253, 1-(7-(2-chlorophenyl)-8-(4- chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-(ethylamino)azetidine-3-carboxamide; PF-95382, 1-(7-(2-chlorophenyl)-8-(4-chloro- phenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-(amino)azetidine-3-carboxamide; CP-945598, 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H- purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide hydrochloride; SR141716A, 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N- (piperidin-1-yl)-1H-pyrazole-3-carboxamide; PF-514273, 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2H- pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one. 0022-3565/10/3351-103–113$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 335, No. 1 Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics 168187/3622552 JPET 335:103–113, 2010 Printed in U.S.A. 103 at ASPET Journals on March 10, 2016 jpet.aspetjournals.org Downloaded from