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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Gauthier JY,Belley M,Deschênes D,Fournier JF,Gagné S,Gareau Y,Hamel M,Hénault M,Hyjazie H,Kargman S,Lavallée G,Levesque JF,Li L,Mamane Y,Mancini J,Morin N,Mulrooney E,Robichaud J,Thérien M,Tranmer G,Wang Z,Wu J

doi

10.1016/j.bmcl.2011.03.081

subject

Has Abstract

pub_date

2011-05-15 00:00:00

pages

2836-9

issue

10

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(11)00400-8

journal_volume

21

pub_type

杂志文章

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