In vivo evaluation of the peripherally selective CB1 receptor antagonist RTI-13329-2 in a mouse model of diet-induced weight gain

Abstract

Cannabinoid receptor 1 (CB1R) antagonists have the potential to treat several important diseases such as obesity, drug addiction, diabetes, and liver disease. Regrettably, central nervous system (CNS) related adverse effects including depression and suicidal ideation were reported with non-tissue selective first generation CB1R antagonists. However, recent studies indicate that primarily targeting peripherally expressed CB1R with antagonists that have limited brain penetration is an attractive strategy for medications development. These compounds are expected to have limited adverse effects in patients while providing the metabolic benefits of CB1R antagonism. Over the last few years, our group has developed several novel CB1R antagonists with limited brain penetration based on the diphenyl purine scaffold of otenabant. One of these compounds, N-{1-[8-(2-Chlorophenyl)-9-(4- chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}methanesulfonamide (RTI-13329-2), was selected for further in vivo studies. RTI-13329-2 is extremely potent with apparent antagonist dissociation constant (Ke) ~ 2.9 nM, CB1R affinity (Ki) ~ 6.2 nM, and >150-fold selectivity for CB1R over CB2R (Fulp et al, J Med Chem, 55, 10022-32, 2012). Further, this compound has excellent metabolic stability, no noticeable interaction with hERG, and minimal effect on CYP3A4 induction. Pharmacokinetic studies indicated that this peripherally selective compound had ~10% brain penetration in both rats and mice. Consequently, RTI-13329-2 was tested in a mouse model of dietinduced weight gain. Male C57BL6 mice at ten weeks of age were fed a high-fat diet (HFD, 60% fat calories) for 4 weeks. Control mice were maintained on a normal diet (10% fat calories). Some animals on HFD were given otenabant (10 mg/kg) or RTI-13329-2 (1 or 10 mg/kg) orally once daily. Body weight and food consumption were closely monitored throughout the study. At the end of four weeks, animals were subjected to oral glucose testing prior to sacrifice. Animals on HFD gained significantly more weight than control animals. Treatment with otenabant and RTI-13329-2 abrogated weight gain in animals and improved glucose tolerance compared to animals on HFD. Livers of animals treated with otenabant and 13329-2 had significantly reduced levels of fat accumulation as well. In conclusion, RTI-13329-2 is a peripherally selective CB1R antagonist that produced beneficial effects in a rodent model of obesity and metabolic syndrome. Refinement of this class of compounds is currently underway.