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

Yang, Peng; Myint, Kyaw-Zeyar; Tong, Qin; Feng, Rentian; Cao, Haiping; Almehizia, Abdulrahman A; Alqarni, Mohammed Hamed; Wang, Lirong; Bartlow, Patrick; Gao, Yingdai; Gertsch, Jürg; Teramachi, Jumpei; Kurihara, Noriyoshi; Roodman, Garson David; Cheng, Tao; Xie, Xiang-Qun (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), pp. 9973-87. Easton, Pa.: American Chemical Society 10.1021/jm301212u

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
UniBE Contributor:	Gertsch, Jürg
ISSN:	0022-2623
Publisher:	American Chemical Society
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:38
Last Modified:	05 Dec 2022 14:11
Publisher DOI:	10.1021/jm301212u
PubMed ID:	23072339
Web of Science ID:	000311461500047
URI:	https://boris.unibe.ch/id/eprint/15267 (FactScience: 222570)