Discovery of aminocyclohexene analogues as selective and orally bioavailable hNav1.7 inhibitors for analgesia |
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| Authors: | Mingxing Teng Wentao Wu Zhixiang Li Guangwen Yang Jian Qin Yikai Wang Zhijing Hu Haiheng Dong Lijuan Hou Guoping Hu Liang Shen Yang Zhang Jian Li Shuhui Chen Jingwei Tian Liang Ye Jianzhao Zhang Hongbo Wang |
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| Institution: | 1. WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People’s Republic of China;2. Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, People’s Republic of China |
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| Abstract: | hNav1.7 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 hNav1.7 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. |
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| Keywords: | Voltage-gated sodium channal Aminocyclohexene Pain Analgesia |
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