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

被引：49

作者：

Yang, Peng ^{[1
,2
,4
,5
]}

Myint, Kyaw-Zeyar ^{[1
,2
,3
,4
,5
]}

Tong, Qin ^{[1
,2
,4
,5
]}

Peng, Rentian ^{[1
,2
,4
,5
]}

Cao, Haiping ^{[1
,2
]}

Almehizia, Abdulrahman A. ^{[1
,2
,4
,5
]}

Alqarni, Mohammed Hamed ^{[1
,2
,4
,5
]}

Wang, Lirong ^{[1
,2
,4
,5
]}

Bartlow, Patrick ^{[1
,2
,4
,5
]}

Gao, Yingdai ^{[7
,8
,9
]}

Gertsch, Juerg ^{[10
]}

Teramachi, Jumpei ^{[11
]}

Kurihara, Noriyoshi ^{[11
]}

Roodman, Garson David ^{[11
]}

Cheng, Tao ^{[7
,8
,9
]}

Xie, Xiang-Qun ^{[1
,2
,3
,4
,5
,6
]}

机构：

[1] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Sch Pharm, Computat Chem Genom Screening Ctr, Pittsburgh, PA 15260 USA

[3] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA

[4] Univ Pittsburgh, Drug Discovery Inst, Pittsburgh, PA 15260 USA

[5] Univ Pittsburgh, Pittsburgh Chem Methods & Lib Dev Ctr, Pittsburgh, PA 15260 USA

[6] Univ Pittsburgh, Dept Struct Biol, Pittsburgh, PA 15260 USA

[7] Chinese Acad Med Sci, State Key Lab Expt Hematol, Inst Hematol, Tianjin 300020, Peoples R China

[8] Chinese Acad Med Sci, Blood Dis Hosp, Tianjin 300020, Peoples R China

[9] Peking Union Med Coll, Tianjin 300020, Peoples R China

[10] Univ Bern, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland

[11] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 22期

基金：

中国国家自然科学基金;

关键词：

CANNABINOID RECEPTOR; IN-VIVO; MOLECULAR CHARACTERIZATION; ENDOCANNABINOID SYSTEM; SR; 144528; LIGANDS; ANTAGONIST; BINDING; ANALOGS; TARGET;

D O I：

10.1021/jm301212u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：9973 / 9987

页数：15

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