| Literature DB >> 24900484 |
Robert L Dow1, Philip A Carpino1, Denise Gautreau1, John R Hadcock1, Philip A Iredale1, Dawn Kelly-Sullivan1, Jeffrey S Lizano1, Rebecca E O'Connor1, Steven R Schneider1, Dennis O Scott1, Karen M Ward1.
Abstract
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.Entities:
Keywords: Obesity; antagonist; cannabinoid receptor; clearance; ligand efficiency; ligand-lipophilicity efficiency; multidrug resistance protein 1; polar surface area
Year: 2012 PMID： 24900484 PMCID： PMC4025874 DOI： 10.1021/ml3000325
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345