期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 22, 页码 4979-4984出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.10.010
关键词
Voltage-gated sodium channal; hNav1.7; Aminocyclohexene; Pain; Analgesia
资金
- National Natural Science Foundation of China [81473188]
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. (C) 2017 Elsevier Ltd. All rights reserved.
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