Novel triaryl sulfonamide derivatives as selective cannabinoid receptor 2 inverse agonists and osteoclast inhibitors: discovery, optimization, and biological evaluation.
Novel triaryl sulfonamide derivatives as selective cannabinoid receptor 2 inverse agonists and osteoclast inhibitors: discovery, optimization, and biological evaluation.
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DOI：
10.1021/jm3017464
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发表时间：
2013-03-14
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;Wang, Lipinig;Peng, Rentian;Almehizia, Abdulrahman A.;Tong, Qin;Myint, Kyaw-Zeyar;Ouyang, Qin;Alqarni, Mohammed Hamed;Wang, Lirong;Xie, Xiang-Qun
大麻素受体作为开发潜在治疗配体的药物靶点越来越受到关注。在这里，我们报告的发现和优化的三芳基磺酰胺作为一个新的系列具有显着的CB2受体的亲和力和选择性。设计、合成了四组三芳基配体用于进一步的结构修饰，并鉴定出八种化合物作为具有高结合亲和力（CB2 Ki < 10 nM）的有效和选择性CB2反向激动剂。其中化合物57对CB2受体的亲和力最强（Ki值为0.5 nM），对CB1受体的选择性最好（选择性指数为2594）。重要的是，57还显示出对破骨细胞形成的有效抑制活性，并且通过细胞活力测定证实其抑制作用不是源自其细胞毒性。最后，三维定量构效关系研究证实了我们的SAR研究结果，三个庞大的基团发挥重要作用的CB2受体结合亲和力。
Cannabinoid receptors have gained more and more attention as drug targets for developing potential therapeutic ligands. Here, we report the discovery and optimization of triaryl sulfonamide as a novel series possessing significant CB2 receptor affinity and selectivity. Four sets of triaryl ligands were designed, synthesized for further structural modifications, and led to the identification of eight compounds as potent and selective CB2 inverse agonists with high binding affinity (CB2 Ki < 10 nM). Especially, compound 57 exhibited the strongest binding affinity on CB2 receptor (CB2 Ki of 0.5 nM) and the best selectivity over CB1 receptor (selectivity index of 2594). Importantly, 57 also showed potent inhibitory activity on osteoclast formation, and was confirmed its inhibition effects were not derived from its cytotoxicity by the cell viability assay. Finally, 3D QSAR studies confirmed our SAR findings that three bulky groups play an important role for CB2 receptor binding affinity.
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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：
3.5
作者：
Huffman, JW;Zengin, G;Martin, BR
通讯作者：
Martin, BR
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