Synthesis and SAR of pyrimidine-based, non-nucleotide P2Y14 receptor antagonists.
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.
Guay, D; Beaulieu, C; Belley, M; Crane, SN; DeLuca, J; Gareau, Y; Hamel, M; Henault, M; Hyjazie, H; Kargman, S; Chan, CC; Xu, L; Gordon, R; Li, L; Mamane, Y; Morin, N; Mancini, J; Thérien, M; Tranmer, G; Truong, VL; Wang, Z; Black, WC
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