Synthesis and SAR of pyrimidine-based, non-nucleotide P2Y14 receptor antagonists

Bioorg Med Chem Lett. 2011 May 15;21(10):2832-5. doi: 10.1016/j.bmcl.2011.03.084. Epub 2011 Mar 30.

Abstract

A weak antagonist of the pyrimidinergic receptor P2Y(14) containing a dihydropyridopyrimidine core was identified through high-throughput screening. Subsequent optimization led to potent, non-UTP competitive antagonists and represent the first reported non-nucleotide antagonists of this receptor. Compound 18q was identified as a 10 nM P2Y(14) antagonist with good oral bioavailability and provided sufficient exposure in mice to be used as a tool for future in vivo studies.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Mice
  • Molecular Structure
  • Pan troglodytes
  • Purinergic P2 Receptor Antagonists / chemical synthesis*
  • Purinergic P2 Receptor Antagonists / chemistry
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Receptors, Purinergic P2 / chemistry*
  • Receptors, Purinergic P2Y
  • Structure-Activity Relationship

Substances

  • P2ry14 protein, mouse
  • Purinergic P2 Receptor Antagonists
  • Pyrimidines
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y