title: Synthesis and SAR of pyrimidine-based, non-nucleotide P2Y14 receptor antagonists.
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.
authors.affiliation: Merck Frosst Center for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Quebec, Canada H9R 4P8.
authors.forename: Daniel
authors.initials: D
authors.lastname: Guay
authors.forename: Christian
authors.initials: C
authors.lastname: Beaulieu
authors.forename: Michel
authors.initials: M
authors.lastname: Belley
authors.forename: Sheldon N
authors.initials: SN
authors.lastname: Crane
authors.forename: Jeancarlo
authors.initials: J
authors.lastname: DeLuca
authors.forename: Yves
authors.initials: Y
authors.lastname: Gareau
authors.forename: Martine
authors.initials: M
authors.lastname: Hamel
authors.forename: Martin
authors.initials: M
authors.lastname: Henault
authors.forename: Huda
authors.initials: H
authors.lastname: Hyjazie
authors.forename: Stacia
authors.initials: S
authors.lastname: Kargman
authors.forename: Chi Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Lijing
authors.initials: L
authors.lastname: Xu
authors.forename: Robert
authors.initials: R
authors.lastname: Gordon
authors.forename: Lianhai
authors.initials: L
authors.lastname: Li
authors.forename: Yael
authors.initials: Y
authors.lastname: Mamane
authors.forename: Nicolas
authors.initials: N
authors.lastname: Morin
authors.forename: Joseph
authors.initials: J
authors.lastname: Mancini
authors.forename: Michel
authors.initials: M
authors.lastname: Thérien
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Tranmer
authors.forename: Vouy Linh
authors.initials: VL
authors.lastname: Truong
authors.forename: Zhaoyin
authors.initials: Z
authors.lastname: Wang
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D051379:Mice; D015394:Molecular Structure; D002679:Pan troglodytes; D058919:Purinergic P2 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry; D018048:Receptors, Purinergic P2 / Q000737:chemistry*; D058470:Receptors, Purinergic P2Y; D013329:Structure-Activity Relationship
chemical_list: C509795:P2ry14 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D011743:Pyrimidines; D018048:Receptors, Purinergic P2; D058470:Receptors, Purinergic P2Y