Discovery of DS-1971a, a Potent, Selective NaV1.7 Inhibitor

J Med Chem. 2020 Sep 24;63(18):10204-10220. doi: 10.1021/acs.jmedchem.0c00259. Epub 2020 May 26.


A highly potent, selective NaV1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.

MeSH terms

  • Analgesics / chemical synthesis
  • Analgesics / therapeutic use*
  • Analgesics / toxicity
  • Animals
  • Drug Discovery
  • Female
  • Humans
  • Hyperalgesia / drug therapy*
  • Macaca fascicularis
  • Male
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • NAV1.7 Voltage-Gated Sodium Channel / metabolism*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / therapeutic use*
  • Pyrazoles / toxicity
  • Pyrimidines / chemical synthesis
  • Pyrimidines / therapeutic use*
  • Pyrimidines / toxicity
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / therapeutic use*
  • Sulfonamides / toxicity
  • Voltage-Gated Sodium Channel Blockers / chemical synthesis
  • Voltage-Gated Sodium Channel Blockers / therapeutic use*
  • Voltage-Gated Sodium Channel Blockers / toxicity


  • Analgesics
  • DS-1971a
  • NAV1.7 Voltage-Gated Sodium Channel
  • Pyrazoles
  • Pyrimidines
  • SCN9A protein, human
  • Scn9a protein, mouse
  • Sulfonamides
  • Voltage-Gated Sodium Channel Blockers