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.