The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists

Bioorg Med Chem Lett. 2014 Jan 1;24(1):72-6. doi: 10.1016/j.bmcl.2013.11.074. Epub 2013 Dec 4.

Abstract

A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrazolopyrimidine 2-methyl-5-((phenylthio)methyl)pyrazolo[1,5-a]pyrimidin-7-ol 1, resulting in the discovery of CXCR2 receptor antagonist 2-benzyl-5-(((2,3-difluorophenyl)thio)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol 14. The SAR was investigated by systematic variation of the pendant thiol, alkyl and pyrimidinol groups. Replacement of the pyrazolopyrimidine core with a triazolo alternative led to a dual series of antagonists with favourable biological and pharmacokinetic properties.

Keywords: COPD; CXCR2; Chemokines; Neutrophils; Pyrazolopyrimidine; Triazolopyrimidine.

MeSH terms

  • Administration, Oral
  • Biological Availability
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, CCR2 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Pyrazoles
  • Pyrimidines
  • Receptors, CCR2