Efficacy of the Hepatotropic Peripheral CB1R Inverse Agonist TM38837 in Rat Models of Obesity and Metabolic Syndrome

Background: Although peripherally restricted cannabinoid 1 receptor (CB1R) inhibitors reportedly have the potential to improve the metabolic profile of obese subjects without the central nervous system (CNS) liabilities of centrally acting compounds, weight loss in rodent studies has generally been modest. However, the hepatotropic CB1R inverse agonist TM38837 was more efficacious than the centrally acting drug rimonabant in diet-induced obese (DIO) mice, which has been attributed to enhanced exposure in hepatocytes. Accordingly, TM388837 was investigated in DIO rats to assess weight-reducing efficacy and other potential metabolic benefits relative to CNS exposure. Methods: TM38837 was administered to DIO rats for 5 weeks to determine the effects on body weight, metabolic and inflammatory plasma markers, and hepatic steatosis. Subsequently, CNS exposure was assessed in lean rats using an immunohistochemical analysis of cFOS induction. Finally, food intake-independent effects on hepatic steatosis and glucose homeostasis were evaluated using obese Zucker rats with pair-fed controls. All studies used rimonabant as comparator. Results: Weight loss comparable to that of rimonabant at an equivalent dose was observed for TM38837 in DIO rats, attributed to a loss of fat mass and driven by a sustained reduction in food intake. However, effects on plasma markers and steatosis were not significant (except leptin) for either compound in this study. Unlike for rimonabant, cFOS induction was not significant in any brain areas of lean rats following treatment with the selected efficacious dose of TM38837. Highly significant reductions in liver fat (cf pair-fed controls) and plasma area under the curve above baseline for insulin (AUCB2Insulin), cf vehicle, were subsequently observed following 8- and 4-week dosing with TM38837, respectively, in obese Zucker rats. Conclusions: Liver-targeted CB1R inverse agonists, such as TM38837, have potential for the treatment of obesity and associated morbidities with generous safety margins from CNS side-effects.