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N,N'-((4-(Dimethylamino)phenyl)methylene)bis(2-phenylacetamide) was discovered by using 3D pharmacophore database searches and was biologically confirmed as a new class of CB(2) inverse agonists. Subsequently, 52 derivatives were designed and synthesized through lead chemistry optimization by modifying the rings A-C and the core structure in further SAR studies. Five compounds were developed and also confirmed as CB(2) inverse agonists with the highest CB(2) binding affinity (CB(2)K(i) of 22-85 nM, EC(50) of 4-28 nM) and best selectivity (CB(1)/CB(2) 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 μM. 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.

journal of medicinal chemistry

Lead Discovery, Chemistry Optimization, and Biological Evaluation Studies of Novel Biamide Derivatives as CB<sub>2</sub> Receptor Inverse Agonists and Osteoclast Inhibitors

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

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