Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a dual P2X(3)/P2X(2/3) antagonist for the treatment of pain

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1628-31. doi: 10.1016/j.bmcl.2009.02.003. Epub 2009 Feb 7.

Abstract

P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X(3) and P2X(2/3) receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X(3)/P2X(2/3) antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X(3)/P2X(2/3) antagonist.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Analgesics / chemical synthesis*
  • Analgesics / pharmacology*
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Drug Evaluation, Preclinical
  • Humans
  • Inhibitory Concentration 50
  • Ions
  • Ligands
  • Models, Chemical
  • Pain / drug therapy*
  • Purinergic P2 Receptor Antagonists*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology*
  • Receptors, Purinergic P2 / chemistry
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Ions
  • Ligands
  • Purinergic P2 Receptor Antagonists
  • Pyrimidines
  • RO-4 compound
  • Receptors, Purinergic P2
  • Adenosine Triphosphate