Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3- a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNa V 1.7 Inhibitors for the Treatment of Pain

J Med Chem. 2018 Jun 14;61(11):4810-4831. doi: 10.1021/acs.jmedchem.7b01826. Epub 2018 May 23.

Abstract

The sodium channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of NaV1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Dogs
  • Drug Design*
  • Drug Stability
  • Humans
  • Kinetics
  • Mice
  • Molecular Conformation
  • NAV1.7 Voltage-Gated Sodium Channel / metabolism*
  • Pain / drug therapy*
  • Pain / metabolism
  • Rats
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Voltage-Gated Sodium Channel Blockers / chemistry*
  • Voltage-Gated Sodium Channel Blockers / pharmacokinetics
  • Voltage-Gated Sodium Channel Blockers / pharmacology*
  • Voltage-Gated Sodium Channel Blockers / therapeutic use

Substances

  • NAV1.7 Voltage-Gated Sodium Channel
  • Sulfonamides
  • Voltage-Gated Sodium Channel Blockers