The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y sub(14)

A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY sub(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) sub(1)4 with a good pharmacokinetic profile.