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

A weak antagonist of the pyrimidinergic receptor P2Y₁₄ 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 10nM P2Y₁₄ antagonist with good oral bioavailability and provided sufficient exposure in mice to be used as a tool for future in vivo studies.