Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB(2)) agonists

作者：Cheng Yuan^*; Albrech Brian K; Brown James; Buchanan John L; Buckner William H; DiMauro Erin F; Emkey Renee; Fremeau Robert T Jr; Harrnange 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

来源：Journal of Medicinal Chemistry, 2008, 51(16): 5019-5034.

DOI：10.1021/jm800463f

The CB(2) 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 phamacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB(2) agonist (CB(2) EC(50) = 93 nM, E(max) = 98%, CB(1) EC(50) > 10 mu M). 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 CB(2) (EC(50) = 2 nM, E(max) = 110%) with excellent pharmacokinetic properties.

• 出版日期2008-8-28