Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1.
Bioorg Med Chem Lett. 2011 May 15;21(10):2836-9. doi: 10.1016/j.bmcl.2011.03.081. Epub 2011 Mar 31.
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.
通过高通量筛选，发现了一种嘧啶受体 P2RY(14) 的弱 UDP 竞争性拮抗剂，其核心为萘甲酸。通过优化得到了一些具有更好活性但药代动力学性质较差的化合物。酰基葡萄糖醛酸化为主要代谢途径。增加取代基的吸电子性质可显著降低葡萄糖醛酸化作用并改善药代动力学特性。进一步优化得到了化合物 38，它是一种 8 nM 的 P2Y(14) 的 UDP 竞争性拮抗剂，具有良好的药代动力学特性。
