New P2X3 receptor antagonists. Part 2: Identification and SAR of quinazolinones

Bioorg Med Chem Lett. 2016 Aug 15;26(16):3905-12. doi: 10.1016/j.bmcl.2016.07.013. Epub 2016 Jul 6.

Abstract

Numerous potent P2X3 antagonists have been discovered and the therapeutic potential of P2X3 antagonism already comprises proof-of-concept data obtained in clinical trials with the most advanced compound. We have lately reported the discovery and optimization of thia-triaza-tricycle compounds with potent P2X3 antagonistic properties. This Letter describes the SAR of a back-up series containing a 4-oxo-quinazoline central ring. The discovery of the highly potent compounds 51 is presented.

Keywords: 4-Oxo-6-aryl-phenethyl-quinazolines; ATP; Chronic cough; Ion channel; Nanomolar activity; P2X3 antagonist; Purinergic receptor; Structure–activity relationship.

MeSH terms

  • 4-Quinolones / chemical synthesis
  • 4-Quinolones / chemistry*
  • 4-Quinolones / metabolism
  • Adenosine Triphosphate / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Protein Binding
  • Purinergic P2X Receptor Antagonists / chemical synthesis
  • Purinergic P2X Receptor Antagonists / chemistry*
  • Purinergic P2X Receptor Antagonists / metabolism
  • Quinazolinones / chemistry*
  • Quinazolinones / metabolism
  • Receptors, Purinergic P2X3 / chemistry
  • Receptors, Purinergic P2X3 / metabolism*
  • Structure-Activity Relationship

Substances

  • 4-Quinolones
  • Purinergic P2X Receptor Antagonists
  • Quinazolinones
  • Receptors, Purinergic P2X3
  • Adenosine Triphosphate