The discovery of tetrahydropyridine analogs as hNav1.7 selective inhibitors for analgesia

Wentao Wu; Zhixiang Li; Guangwen Yang; Mingxing Teng; Jian Qin; Zhijing Hu; Lijuan Hou; Liang Shen; Haiheng Dong; Yang Zhang; Jian Li; Shuhui Chen; Jingwei Tian; Jianzhao Zhang; Liang Ye

doi:10.1016/j.bmcl.2017.03.043

The discovery of tetrahydropyridine analogs as hNav1.7 selective inhibitors for analgesia

Bioorg Med Chem Lett. 2017 May 15;27(10):2210-2215. doi: 10.1016/j.bmcl.2017.03.043. Epub 2017 Mar 18.

Authors

Wentao Wu¹, Zhixiang Li¹, Guangwen Yang¹, Mingxing Teng¹, Jian Qin¹, Zhijing Hu¹, Lijuan Hou¹, Liang Shen¹, Haiheng Dong¹, Yang Zhang², Jian Li¹, Shuhui Chen¹, Jingwei Tian³, Jianzhao Zhang⁴, Liang Ye⁴

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: [email protected].
³ 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: [email protected].
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.

PMID: 28385504
DOI: 10.1016/j.bmcl.2017.03.043

Abstract

hNav1.7 small molecular inhibitors have attracted lots of attention by its unique analgesic effect. Herein, we report the design and synthesis of a novel series of tetrahydropyridine analogs as hNav1.7 inhibitors for analgesia. Detail structural-activity relationship (SAR) studies were undertaken towards improving hNav1.7 activity, in vitro ADME, and in vivo PK profiles. These efforts resulted in the identification of compound (-)-15h, a highly potent and selective hNav1.7 inhibitor with good ADME and PK profiles.

Keywords: Analgesia; Pain; Tetrahydropyridine; Voltage-gated sodium channel; hNav1.7.

Publication types

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

MeSH terms

Analgesics / chemical synthesis
Analgesics / chemistry*
Analgesics / pharmacokinetics
Animals
Binding Sites
Cytochrome P-450 CYP2C9 / chemistry
Cytochrome P-450 CYP2C9 / metabolism
Drug Design
Half-Life
Humans
Inhibitory Concentration 50
Molecular Docking Simulation
NAV1.7 Voltage-Gated Sodium Channel / chemistry
NAV1.7 Voltage-Gated Sodium Channel / metabolism*
Protein Structure, Tertiary
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacokinetics
Rats
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / pharmacokinetics
Voltage-Gated Sodium Channel Blockers / chemical synthesis
Voltage-Gated Sodium Channel Blockers / chemistry*
Voltage-Gated Sodium Channel Blockers / pharmacokinetics

Substances

Analgesics
NAV1.7 Voltage-Gated Sodium Channel
Pyridines
Sulfonamides
Voltage-Gated Sodium Channel Blockers
Cytochrome P-450 CYP2C9
pyridine