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ACS Med Chem Lett. 2012 Mar 21;3(5):397-401. doi: 10.1021/ml3000325. eCollection 2012 May 10.

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

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Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.


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 (3) 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.


Obesity; antagonist; cannabinoid receptor; clearance; ligand efficiency; ligand-lipophilicity efficiency; multidrug resistance protein 1; polar surface area

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