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

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

doi:10.1016/j.bmcl.2017.10.010

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

Bioorg Med Chem Lett. 2017 Nov 15;27(22):4979-4984. doi: 10.1016/j.bmcl.2017.10.010. Epub 2017 Oct 7.

Authors

Mingxing Teng¹, Wentao Wu², Zhixiang Li¹, Guangwen Yang¹, Jian Qin¹, Yikai Wang¹, Zhijing Hu¹, Haiheng Dong¹, Lijuan Hou¹, Guoping Hu¹, Liang Shen¹, Yang Zhang³, Jian Li¹, Shuhui Chen¹, Jingwei Tian⁴, Liang Ye⁵, Jianzhao Zhang⁵, Hongbo Wang⁵

Affiliations

¹ WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
² WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China. Electronic address: wu_wentao@wuxiapptec.com.
³ WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China. Electronic address: zhang_yang@wuxiapptec.com.
⁴ 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. Electronic address: Tianjingwei@luye.com.
⁵ 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.

PMID: 29037948
DOI: 10.1016/j.bmcl.2017.10.010

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.

Keywords: Aminocyclohexene; Analgesia; Pain; Voltage-gated sodium channal; hNav1.7.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
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
Inhibitory Concentration 50
Molecular Docking Simulation
NAV1.7 Voltage-Gated Sodium Channel / chemistry*
NAV1.7 Voltage-Gated Sodium Channel / metabolism
Pain / drug therapy
Protein Structure, Tertiary
Rats
Stereoisomerism
Structure-Activity Relationship
Voltage-Gated Sodium Channel Blockers / chemistry*
Voltage-Gated Sodium Channel Blockers / pharmacokinetics
Voltage-Gated Sodium Channel Blockers / therapeutic use

Substances

Analgesics
Cyclohexenes
NAV1.7 Voltage-Gated Sodium Channel
Voltage-Gated Sodium Channel Blockers
cyclohexene
Cytochrome P-450 CYP2C9