Discovery of Potent, Selective, and State-Dependent Na V 1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides

J Med Chem. 2020 Jun 11;63(11):6107-6133. doi: 10.1021/acs.jmedchem.0c00361. Epub 2020 May 19.

Abstract

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.

MeSH terms

  • Animals
  • Chromans / chemistry*
  • Chromans / pharmacokinetics
  • Chromans / therapeutic use
  • Cytochrome P-450 CYP2C9 / chemistry
  • Cytochrome P-450 CYP2C9 / metabolism
  • Cytochrome P-450 CYP3A / chemistry
  • Cytochrome P-450 CYP3A / metabolism
  • Disease Models, Animal
  • Drug Design
  • Drug Evaluation, Preclinical
  • Half-Life
  • Male
  • Mice
  • Mice, Inbred BALB C
  • NAV1.7 Voltage-Gated Sodium Channel / chemistry
  • NAV1.7 Voltage-Gated Sodium Channel / metabolism*
  • Neuralgia / chemically induced
  • Neuralgia / drug therapy
  • Neuralgia / pathology
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / therapeutic use
  • Voltage-Gated Sodium Channel Blockers / chemistry*
  • Voltage-Gated Sodium Channel Blockers / pharmacokinetics
  • Voltage-Gated Sodium Channel Blockers / therapeutic use

Substances

  • Chromans
  • NAV1.7 Voltage-Gated Sodium Channel
  • Protein Isoforms
  • Sulfonamides
  • Voltage-Gated Sodium Channel Blockers
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP3A