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.

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