1051372-08-7Relevant academic research and scientific papers
Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB 2) agonists
Cheng, Yuan,Albrecht, Brian K.,Brown, James,Buchanan, John L.,Buckner, William H.,DiMauro, Erin F.,Emkey, Renee,Fremeau Jr., Robert T.,Harmange, Jean-Christophe,Hoffman, Beth J.,Huang, Liyue,Huang, Ming,Lee, Josie Han,Lin, Fen-Fen,Martin, Matthew W.,Nguyen, Hung Q.,Patel, Vinod F.,Tomlinson, Susan A.,White, Ryan D.,Xia, Xiaoyang,Hitchcock, Stephen A.
experimental part, p. 5019 - 5034 (2009/07/19)
The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB 2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB 1 EC50 > 10 μM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties.
Structural modifications of N-arylamide oxadiazoles: Identification of N-arylpiperidine oxadiazoles as potent and selective agonists of CB2
DiMauro, Erin F.,Buchanan, John L.,Cheng, Alan,Emkey, Renee,Hitchcock, Stephen A.,Huang, Liyue,Huang, Ming Y.,Janosky, Brett,Lee, Josie H.,Li, Xingwen,Martin, Matthew W.,Tomlinson, Susan A.,White, Ryan D.,Zheng, Xiao Mei,Patel, Vinod F.,Fremeau Jr., Robert T.
scheme or table, p. 4267 - 4274 (2009/04/07)
Structural modifications to the central portion of the N-arylamide oxadiazole scaffold led to the identification of N-arylpiperidine oxadiazoles as conformationally constrained analogs that offered improved stability and comparable potency and selectivity. The simple, modular scaffold allowed for the use of expeditious and divergent synthetic routes, which provided two-directional SAR in parallel. Several potent and selective agonists from this novel ligand class are described.
