Synthesis and Pharmacological Characterization of Novel Peripheral Cannabinoid-1 Receptor Blockers Based on a Tricyclic Scaffold

The development of peripherally selective cannabinoid-1 receptor (CB₁R) antagonists offers a promising strategy for obesity treatment. Here, we evaluated the efficacy of novel tricyclic CB₁R antagonists, focusing on BNS808. Our findings demonstrate that BNS808 exhibits robust CB₁R antagonism with notable CB₂R selectivity, minimal brain penetration, and potent in vitro and in vivo efficacy. The compound’s high plasma protein binding reduces free drug availability for CNS entry, enhancing safety and minimizing drug-drug interactions. In diet-induced obese mice, BNS808 effectively reduced body weight, adiposity, liver triglycerides, and liver enzymes, supporting its peripherally mediated action. These results highlight BNS808 as a promising candidate for obesity treatment. Additionally, our novel library of peripherally selective CB₁R antagonists provides a strong foundation for future drug development. With further refinement, BNS808 holds significant clinical potential to address the global obesity epidemic.