4-((3,5-Dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoic acid (ZL006, 1) is a small-molecular inhibitor of the nNOS/PSD-95 interaction, that is under preclinical evaluation stage for cerebral ischemia. However, the fast metabolism and low permeability across the blood brain barrier (BBB) have restricted its further use. In this manuscript, the mass spectroscopy analysis showed that ZL006 mainly combined with glucuronic acid in mice plasma, which accelerated its metabolism and elimination. Hence, six ZL006 analogs were designed according to the probable metabolism sites of ZL006, and featured the alkylation at phenolic hydroxyl, secondary amine and carboxyl groups. These compounds were synthesized in moderate to good yields, and fully characterized with ¹H NMR and MS. Further metabolism investigation of ZL006 analogs showed that phenolic hydroxyl group of aromatic ring A was the major conjugation site with glucuronic acid, and ZL006 cyclohexyl ester (6) had a better permeability across BBB, which was a potent prodrug for cerebral ischemia.

4 - （（3,5-二氯-2-羟基苄基）氨基）-2-羟基苯甲酸（ZL006，1）是nNOS的/ PSD-95的相互作用，也就是处于临床前评估阶段为脑缺血的小分子抑制剂。但是，新陈代谢的快速性和跨血脑屏障（BBB）的低渗透性限制了它的进一步使用。在该手稿中，质谱分析表明ZL006主要与葡萄糖醛酸在小鼠血浆中结合，从而加速了其代谢和清除。因此，根据ZL006可能的代谢位点设计了六个ZL006类似物，并以酚羟基，仲胺和羧基上的烷基化为特征。这些化合物的合成产率中等至良好，并通过^1进行了全面表征1 H NMR和MS。ZL006类似物的进一步代谢研究表明，芳香环A的酚羟基是与葡萄糖醛酸的主要缀合位点，ZL006环己酯（6）对BBB的通透性更好，这是脑缺血的有效前药。