Discovery of ONO-8590580: A novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127536. doi: 10.1016/j.bmcl.2020.127536. Epub 2020 Sep 6.

Abstract

The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABAA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580.

Keywords: Cognition enhancement; GABAA α5; Negative allosteric modulator; ONO-8590580.

MeSH terms

  • Allosteric Regulation / drug effects
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Receptors, GABA-A / metabolism*
  • Structure-Activity Relationship

Substances

  • GABRA5 protein, human
  • Imidazoles
  • ONO-8590580
  • Pyridines
  • Receptors, GABA-A