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  • Title: Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists.
    Author: Cheng Y, Albrecht BK, Brown J, Buchanan JL, Buckner WH, DiMauro EF, Emkey R, Fremeau RT, Harmange JC, Hoffman BJ, Huang L, Huang M, Lee JH, Lin FF, Martin MW, Nguyen HQ, Patel VF, Tomlinson SA, White RD, Xia X, Hitchcock SA.
    Journal: J Med Chem; 2008 Aug 28; 51(16):5019-34. PubMed ID: 18680277.
    Abstract:
    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 CB2 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%, CB1 EC50 > 10 microM). 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.
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