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.
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DOI：
10.1021/jm301212u
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发表时间：
2012-11-26
影响因子：
7.3
通讯作者：
Xie, Xiang-Qun
中科院分区：
文献类型：
--
作者：
Yang, Peng;Myint, Kyaw-Zeyar;Tong, Qin;Peng, Rentian;Cao, Haiping;Almehizia, Abdulrahman A.;Alqarni, Mohammed Hamed;Wang, Lirong;Bartlow, Patrick;Gao, Yingdai;Gertsch, Juerg;Teramachi, Jumpei;Kurihara, Noriyoshi;Roodman, Garson David;Cheng, Tao;Xie, Xiang-Qun
N，N′-（（4-（Dimethylamino）phenyl）methylene）bis（2-phenylacetamide）是通过三维药效团数据库检索发现的一类新的CB 2反向激动剂。随后，在进一步的SAR研究中，通过对A-C环和核心结构的修饰，通过先导化学优化，设计并合成了52个衍生物。开发了五种化合物，并确认为CB 2反向激动剂，具有最高的CB 2结合亲和力（CB 2 Ki为22-85 nM，EC 50为4-28 nM）和最佳选择性（CB 1/CB 2为235至909倍）。破骨细胞生成实验表明，PAM化合物对破骨细胞的生成有明显的抑制作用。特别是，化合物26即使在0.1 μM的低浓度下也显示出72%的抑制活性。细胞毒性实验表明，PAM化合物对破骨细胞生成的抑制作用不是由于其细胞毒性。因此，这些PAM衍生物可作为开发新型抗骨质疏松剂的潜在先导。
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 Ki 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 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.
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影响因子：
5.6
作者：
Myint KZ;Xie XQ
通讯作者：
Xie XQ
影响因子：
7.3
作者：
Diaz, Philippe;Phatak, Sharangdhar S.;Naguib, Mohamed
通讯作者：
Naguib, Mohamed
影响因子：
5.7
作者：
Feng, Rentian;Ma, Huihui;Lentzsch, Suzanne
通讯作者：
Lentzsch, Suzanne
DOI：
10.1073/pnas.0803601105
发表时间：
2008-07-01
影响因子：
11.1
作者：
Gertsch, Juerg;Leonti, Marco;Zimmer, Andreas
通讯作者：
Zimmer, Andreas
影响因子：
3.4
作者：
Hohmann, AG
通讯作者：
Hohmann, AG