Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
J Med Chem. 2013 Mar 14;56(5):2045-58. doi: 10.1021/jm3017464. Epub 2013 Mar 1.
Cannabinoid receptors have gained increasing attention as drug targets for developing potential therapeutic ligands. Here, we report the discovery and optimization of triaryl sulfonamides as a novel series possessing significant CB2 receptor affinity and selectivity. Four sets of triaryl ligands were designed and synthesized for further structural modifications and led to the identification of eight compounds as potent and selective CB2 inverse agonists with high binding affinity (CB2K(i) < 10 nM). Especially, compound 57 exhibited the strongest binding affinity on the CB2 receptor (CB2K(i) of 0.5 nM) and the best selectivity over the CB1 receptor (selectivity index of 2594). Importantly, 57 also showed potent inhibitory activity on osteoclast formation, and it was confirmed by a cell viability assay that the inhibition effects were not derived from the cytotoxicity. Finally, 3D QSAR studies confirmed our SAR findings that three bulky groups play an important role for CB2 receptor binding affinity.
大麻素受体作为开发潜在治疗性配体的药物靶点受到了越来越多的关注。在这里，我们报告了三芳基磺酰胺作为一个新型系列的发现和优化，该系列具有显著的 CB2 受体亲和力和选择性。设计并合成了四组三芳基配体，以进一步进行结构修饰，从而鉴定出八种化合物作为具有高结合亲和力（CB2K(i)<10 nM）的有效和选择性 CB2 反向激动剂。特别是化合物 57 在 CB2 受体上表现出最强的结合亲和力（CB2K(i)为 0.5 nM），并且对 CB1 受体具有最佳的选择性（选择性指数为 2594）。重要的是，57 还表现出对破骨细胞形成的有效抑制活性，细胞活力测定证实抑制作用不是源于细胞毒性。最后，3D QSAR 研究证实了我们的 SAR 发现，即三个大体积基团对 CB2 受体结合亲和力起着重要作用。
