Discovery of HN37 as a Potent and Chemically Stable Antiepileptic Drug Candidate

J Med Chem. 2021 May 13;64(9):5816-5837. doi: 10.1021/acs.jmedchem.0c02252. Epub 2021 Apr 30.

Abstract

We previously reported that P-retigabine (P-RTG), a retigabine (RTG) analogue bearing a propargyl group at the nitrogen atom in the linker of RTG, displayed moderate anticonvulsant efficacy. Recently, our further efforts led to the discovery of HN37 (pynegabine), which demonstrated satisfactory chemical stability upon deleting the ortho liable -NH2 group and installing two adjacent methyl groups to the carbamate motif. HN37 exhibited enhanced activation potency toward neuronal Kv7 channels and high in vivo efficacy in a range of pre-clinical seizure models, including the maximal electroshock test and a 6 Hz model of pharmacoresistant limbic seizures. With its improved chemical stability, strong efficacy, and better safety margin, HN37 has progressed to clinical trial in China for epilepsy treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / chemistry*
  • Anticonvulsants / therapeutic use
  • Carbamates / chemistry*
  • Carbamates / metabolism
  • Carbamates / therapeutic use
  • Disease Models, Animal
  • Dogs
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Drug Stability
  • Electroshock
  • Half-Life
  • Humans
  • KCNQ Potassium Channels / chemistry
  • KCNQ Potassium Channels / metabolism
  • Mice
  • Phenylenediamines / chemistry
  • Phenylenediamines / metabolism
  • Phenylenediamines / therapeutic use
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / drug therapy
  • Seizures / etiology
  • Structure-Activity Relationship

Substances

  • Anticonvulsants
  • Carbamates
  • KCNQ Potassium Channels
  • Phenylenediamines
  • Protein Isoforms
  • ezogabine