title: The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14.
abstract: A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Jacques Yves
authors.initials: JY
authors.lastname: Gauthier
authors.forename: Michel
authors.initials: M
authors.lastname: Belley
authors.forename: Denis
authors.initials: D
authors.lastname: Deschênes
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fournier
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gagné
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: Hénault
authors.forename: Huda
authors.initials: H
authors.lastname: Hyjazie
authors.forename: Stacia
authors.initials: S
authors.lastname: Kargman
authors.forename: Geneviève
authors.initials: G
authors.lastname: Lavallée
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Levesque
authors.forename: Lianhai
authors.initials: L
authors.lastname: Li
authors.forename: Yaël
authors.initials: Y
authors.lastname: Mamane
authors.forename: Joseph
authors.initials: J
authors.lastname: Mancini
authors.forename: Nicolas
authors.initials: N
authors.lastname: Morin
authors.forename: Erin
authors.initials: E
authors.lastname: Mulrooney
authors.forename: Joël
authors.initials: J
authors.lastname: Robichaud
authors.forename: Michel
authors.initials: M
authors.lastname: Thérien
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Tranmer
authors.forename: Zhaoyin
authors.initials: Z
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002679:Pan troglodytes; D011485:Protein Binding / Q000187:drug effects; D058919:Purinergic P2 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018048:Receptors, Purinergic P2; D058470:Receptors, Purinergic P2Y; D013329:Structure-Activity Relationship; D014530:Uridine Diphosphate
chemical_list: D002264:Carboxylic Acids; D009281:Naphthalenes; C509795:P2ry14 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058470:Receptors, Purinergic P2Y; C085312:1-naphthoic acid; D014530:Uridine Diphosphate