Discovery and Optimization of a Novel Series of N-Arylamide Oxadiazoles as Potent, Highly Selective and Orally Bioavailable Cannabinoid Receptor 2 (CB2) Agonists

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• 作者：Yuan Cheng ; Brian K. Albrecht ; James Brown ; John L. Buchanan ; William H. Buckner ; Erin F. DiMauro ; Renee Emkey ; Robert T. Fremeau ; ; Jean-Christophe Harmange ; Beth J. Hoffman ; Liyue Huang ; Ming Huang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：August 28, 2008
• 年：2008
• 卷：51
• 期：16
• 页码：5019-5034
• 全文大小：387K
• 年卷期：v.51,no.16(August 28, 2008)
• ISSN：1520-4804

文摘

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, E_max = 98%, CB₁ 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, E_max = 110%) with excellent pharmacokinetic properties.