Lead Discovery, Chemistry Optimization, and Biological Evaluation Studies of Novel Biamide Derivatives as CB2 Receptor Inverse Agonists and Osteoclast Inhibitors

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• 作者：Peng Yang ; Kyaw-Zeyar Myint ; Qin Tong ; Rentian Feng ; Haiping Cao ; Abdulrahman A. Almehizia ; Mohammed Hamed Alqarni ; Lirong Wang ; Patrick Bartlow ; Yingdai Gao ; J眉rg Gertsch ; Jumpei Teramachi ; Noriyoshi Kurihara ; Garson David Roodman ; Tao Cheng ; Xiang-Qun Xie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9973-9987
• 全文大小：576K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

N,N鈥?((4-(Dimethylamino)phenyl)methylene)bis(2-phenylacetamide) was discovered by using 3D pharmacophore database searches and was biologically confirmed as a new class of CB₂ inverse agonists. Subsequently, 52 derivatives were designed and synthesized through lead chemistry optimization by modifying the rings A鈥揅 and the core structure in further SAR studies. Five compounds were developed and also confirmed as CB₂ inverse agonists with the highest CB₂ binding affinity (CB₂K_i of 22鈥?5 nM, EC₅₀ of 4鈥?8 nM) and best selectivity (CB₁/CB₂ of 235- to 909-fold). Furthermore, osteoclastogenesis bioassay indicated that PAM compounds showed great inhibition of osteoclast formation. Especially, compound 26 showed 72% inhibition activity even at the low concentration of 0.1 渭M. The cytotoxicity assay suggested that the inhibition of PAM compounds on osteoclastogenesis did not result from its cytotoxicity. Therefore, these PAM derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent.