Discovery of NR2B-selective antagonists via scaffold hopping and pharmacokinetic profile optimization

Bioorg Med Chem Lett. 2019 May 1;29(9):1143-1147. doi: 10.1016/j.bmcl.2019.02.017. Epub 2019 Feb 15.

Abstract

Selective N-methyl-d-aspartate receptor subunit 2B (NR2B) antagonists show potential as analgesic drugs, and do not cause side effects associated with non-selective N-methyl-d-aspartate (NMDA) antagonists. Using a scaffold-hopping approach, we previously identified isoxazole derivative 4 as a potent selective NR2B antagonist. In this study, further scaffold hopping of isoxazole derivative 4 and optimization of its pharmacokinetic profile led to the discovery of the orally bioavailable compound 6v. In a rat study of analgesia, 6v demonstrated analgesic effects against neuropathic pain.

Keywords: Analgesic activity; NMDA receptor antagonist; Scaffold hopping.

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacokinetics
  • Analgesics / pharmacology*
  • Animals
  • Drug Design*
  • Male
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Analgesics
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate