Discovery of aminocyclohexene analogues as selective and orally bioavailable hNav1.7 inhibitors for analgesia

[Display omitted] 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 opti...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-11, Vol.27 (22), p.4979-4984
Main 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
Format: Article
Language:English
Subjects:
Administration, Oral
Aminocyclohexene
Analgesia
Analgesics - chemistry
Analgesics - pharmacokinetics
Analgesics - therapeutic use
Animals
Binding Sites
Cyclohexenes - chemistry
Cyclohexenes - pharmacokinetics
Cyclohexenes - therapeutic use
Cytochrome P-450 CYP2C9 - chemistry
Cytochrome P-450 CYP2C9 - metabolism
Disease Models, Animal
Drug Evaluation, Preclinical
Half-Life
hNav1.7
Inhibitory Concentration 50
Molecular Docking Simulation
NAV1.7 Voltage-Gated Sodium Channel - chemistry
NAV1.7 Voltage-Gated Sodium Channel - metabolism
Pain
Pain - drug therapy
Protein Structure, Tertiary
Rats
Stereoisomerism
Structure-Activity Relationship
Voltage-gated sodium channal
Voltage-Gated Sodium Channel Blockers - chemistry
Voltage-Gated Sodium Channel Blockers - pharmacokinetics
Voltage-Gated Sodium Channel Blockers - therapeutic use
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.10.010