Identification and SAR of novel diaminopyrimidines. Part 2: The discovery of RO-51, a potent and selective, dual P2X(3)/P2X(2/3) antagonist for the treatment of pain

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1632-5. doi: 10.1016/j.bmcl.2009.01.097. Epub 2009 Feb 4.

Abstract

The purinoceptor subtypes P2X(3) and P2X(2/3) have been shown to play a pivotal role in models of various pain conditions. Identification of a potent and selective dual P2X(3)/P2X(2/3) diaminopyrimidine antagonist RO-4 prompted subsequent optimization of the template. This paper describes the SAR and optimization of the diaminopyrimidine ring and particularly the substitution of the 2-amino group. The discovery of the highly potent and drug-like dual P2X(3)/P2X(2/3) antagonist RO-51 is presented.

MeSH terms

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

Substances

  • Analgesics
  • Purinergic P2 Receptor Antagonists
  • Pyrimidines
  • RO-51 compound
  • Receptors, Purinergic P2
  • Adenosine Triphosphate