1 research outputs found
Design of a Potent CB<sub>1</sub> Receptor Antagonist Series: Potential Scaffold for Peripherally-Targeted Agents
Antagonism of cannabinoid-1 (CB<sub>1</sub>) receptor
signaling
has been demonstrated to inhibit feeding behaviors in humans, but
CB<sub>1</sub>-mediated central nervous system (CNS) side effects
have halted the marketing and further development of the lead drugs
against this target. However, peripherally restricted CB<sub>1</sub> 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
CB<sub>1</sub> 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 CB<sub>1</sub> receptor antagonists