期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 21, 期 10, 页码 2836-2839出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.03.081
关键词
Pyrimidinergic receptor; P2Y14; GPR105; Competitive antagonist; SAR; Glucuronidation
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. (C) 2011 Elsevier Ltd. All rights reserved.
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