Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy., Kirkland, Quebec, Canada H9H 3L1.
Bioorg Med Chem Lett. 2011 Jul 15;21(14):4366-8. doi: 10.1016/j.bmcl.2010.12.113. Epub 2010 Dec 28.
Our series of competitive antagonists against the G-protein coupled receptor P2Y(14) were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.
我们一系列针对 G 蛋白偶联受体 P2Y(14)的竞争性拮抗剂在血清存在下（>99%的蛋白结合）发现高度结合。开发了一种使用 2%人血清白蛋白 (HSA) 的结合测定法来指导进一步的 SAR 研究，并导致鉴定出两性离子 2，其与我们之前的先导化合物 1（323 倍）相比明显移位（18 倍）小。然而，由于 2 的生物利用度低，因此制备了酯前药库（7a-7j）并进行了体外评估。然后对最有趣的候选物进行体内分析，并鉴定出前药 7j，其具有明显改善的药代动力学特征。
