Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 22, Pages 9973-9987Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm301212u
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Funding
- NIH [R01DA025612, T32 EB009403]
- National Natural Science Foundation of China [NSFC81090410, NSFC90913018]
- Joint CMU-Pitt computational biology Ph.D. program
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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 CB2 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 CB2 inverse agonists with the highest CB2 binding affinity (CB2 K-i of 22-85 nM, EC50 of 4-28 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 mu 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.
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