The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3285-90. doi: 10.1016/j.bmcl.2014.06.011. Epub 2014 Jun 14.

Abstract

A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrimidine 2-((2,6-dichlorobenzyl)thio)-5-isocyano-6-phenylpyrimidin-4-ol 4, resulting in the discovery of CXCR2 receptor antagonist 2-((2,3-difluorobenzyl)thio)-6-(2-(hydroxymethyl)cyclopropyl)-5-isocyanopyrimidin-4-ol 24. The SAR was investigated by systematic variation of the aromatic group at c-6, the linker between c-2 and the halogenated ring, and the c-5 nitrile moiety.

Keywords: COPD; CXCR2; Chemokines; Neutrophils; Pyrimidine.

MeSH terms

  • Administration, Oral
  • Biological Availability
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, Interleukin-8B / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 2-((2,3-difluorobenzyl)thio)-6-(2-(hydroxymethyl)cyclopropyl)-5-isocyanopyrimidin-4-ol
  • Pyrimidines
  • Receptors, Interleukin-8B