Design of a Potent CB₁ Receptor Antagonist Series: Potential Scaffold for Peripherally-Targeted Agents

Antagonism of cannabinoid-1 (CB₁) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB₁-mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB₁ receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure–activity-relationship analysis of a novel bicyclic scaffold (<b>3</b>) that exhibits potent CB₁ receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB₁ receptor antagonists