Discovery of aminocyclohexene analogues as selective and orally bioavailable hNav1.7 inhibitors for analgesia. Issue 22 (15th November 2017)

• Record Type: Journal Article
• Authors: Teng, Mingxing; Wu, Wentao; Li, Zhixiang; Yang, Guangwen; Qin, Jian; Wang, Yikai; Hu, Zhijing; Dong, Haiheng; Hou, Lijuan; Hu, Guoping; Shen, Liang; Zhang, Yang; Li, Jian; Chen, Shuhui; Tian, Jingwei; Ye, Liang; Zhang, Jianzhao; Wang, Hongbo
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 22(2017)
• Page Start: 4979
• Page End: 4984
• Publication Date: 2017-11-15
• Subjects: Voltage-gated sodium channal -- hNav1.7 -- Aminocyclohexene -- Pain -- Analgesia; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.10.010
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: h Nav1.7 receives a lot of attention owing to its attractive mechanism of action in pain processing pathway. We have previously reported our design of a novel series of tetrahydropyridine analogues towards h Nav1.7 selective inhibitors. Herein, we disclose further efforts to the optimization of hit compound (−)-6, which led to the identification of aminocyclohexene analogues (−)-9 and (−)-17 with good potency, high selectivity, and minimal CYP inhibition. Both compounds (−)-9 and (−)-17 demonstrated improved pharmacokinetic profiles in rats, and robust efficacy in rat formalin-induced nociception and spinal nerve ligation (SNL) models.