The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14.
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.
Gauthier, JY; Belley, M; Deschênes, D; Fournier, J-F; Gagné, S; Gareau, Y; Hamel, M; Hénault, M; Hyjazie, H; Kargman, S; Lavallée, G; Levesque, J-F; Li, L; Mamane, Y; Mancini, J; Morin, N; Mulrooney, E; Robichaud, J; Thérien, M; Tranmer, G; Wang, Z; Wu, J; Black, WC
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