Lead discovery, chemistry optimization, and biological evaluation studies of novel biamide derivatives as CB2 receptor inverse agonists and osteoclast inhibitors

Peng Yang, Kyaw Zeyar Myint, Qin Tong, Rentian Feng, Haiping Cao, Abdulrahman A. Almehizia, Mohammed Hamed Alqarni, Lirong Wang, Patrick Bartlow, Yingdai Gao, Jürg Gertsch, Jumpei Teramachi, Noriyoshi Kurihara, Garson David Roodman, Tao Cheng, Xiang Qun Xie

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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 (CB2Ki of 22-85 nM, EC50 of 4-28 nM) and best selectivity (CB 1/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 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.

Original languageEnglish (US)
Pages (from-to)9973-9987
Number of pages15
JournalJournal of Medicinal Chemistry
Volume55
Issue number22
DOIs
StatePublished - Nov 26 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Yang, P., Myint, K. Z., Tong, Q., Feng, R., Cao, H., Almehizia, A. A., Alqarni, M. H., Wang, L., Bartlow, P., Gao, Y., Gertsch, J., Teramachi, J., Kurihara, N., Roodman, G. D., Cheng, T., & Xie, X. Q. (2012). Lead discovery, chemistry optimization, and biological evaluation studies of novel biamide derivatives as CB2 receptor inverse agonists and osteoclast inhibitors. Journal of Medicinal Chemistry, 55(22), 9973-9987. https://doi.org/10.1021/jm301212u