The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain

Bioorg Med Chem. 2019 Jan 1;27(1):230-239. doi: 10.1016/j.bmc.2018.12.002. Epub 2018 Dec 4.

Abstract

The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.

Keywords: Benzimidazole; Inflammatory pain; Na(V)1.8; Neuropathic pain; PF-06305591; SCN10A; Voltage gated sodium channel.

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology*
  • Drug Design
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • NAV1.8 Voltage-Gated Sodium Channel / metabolism*
  • Solubility
  • Structure-Activity Relationship
  • Voltage-Gated Sodium Channel Blockers / chemical synthesis
  • Voltage-Gated Sodium Channel Blockers / chemistry
  • Voltage-Gated Sodium Channel Blockers / pharmacokinetics
  • Voltage-Gated Sodium Channel Blockers / pharmacology*

Substances

  • Benzimidazoles
  • NAV1.8 Voltage-Gated Sodium Channel
  • Voltage-Gated Sodium Channel Blockers