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

Abstract

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.Cannabinoid-1 receptor (CB1R) is a G protein-coupled receptor predominantly expressed in the nervous system, and it has been identified as the brain receptor for exogenous molecules such as tetrahydrocannabinol (Berry and Mechoulam, 2002;Howlett et al., 2002;Pertwee, 2005;Thakur et al.,

The Discovery of Taranabant, a Selective Cannabinoid‐1 Receptor Inverse Agonist for the Treatment of Obesity

“…These efforts led to the identification of a novel, acyclic amide with excellent CB1R potency and selectivity. The rapid preparation of analogues was facilitated by relatively straightforward synthetic methodologies and a high throughput pharmacodynamic assay qualified interesting compounds for further study [6,17]. A potential safety issue was identified early in the program: high covalent protein binding can lead to idiosyncratic allergic drug reactions.…”

“…In the case of the CB1 receptor, demonstrating receptor occupancy and correlating it with efficacy, in this case reductions in food intake and body weight, was considered very important to success of the program. In preclinical studies in rats, receptor occupancy by 32 was determined ex vivo and correlated with weight loss [17]. Partial receptor occupancy (30 -40%) of the CB1R in the brain was sufficient to cause weight loss in rats.…”

“…Compound 32 was chosen for development as MK-0364 and became taranabant. A detailed report of its preclinical profile has been published and selected data is summarized in Table 3 [17]. Taranabant is currently in late-stage human clinical trials for the treatment of obesity and related disorders [18].…”

“…170 nM; general screening: 7 hits a 10 uM), had good pharmacokinetics (rat: F = 75%, t 1/2 = 2.7 h, Cl p = 33 mL/ min/kg), and worked well in overnight food intake / body weight reduction in DIO rats (FI -55% @ 3 mg/kg p.o.). A high throughput pharmacodynamic assay guided much of the early SAR development [6,17]. The CB1R/CB2R agonist CP99540 (1 mg/kg ip.)…”

Development of a Population Pharmacokinetic Model for Taranabant, a Cannibinoid-1 Receptor Inverse Agonist

“…Taranabant is a potent and selective cannabinoid-1 receptor inverse agonist that has demonstrated a dose-dependent inhibition of food intake and weight gain, resulting in weight loss and decreased fat mass in preclinical models of obesity (1). In the clinical setting, taranabant reduced acute food intake over 24 h and increased energy expenditure between 2 and 5 h postdose versus placebo in overweight and obese male volunteers (2).…”