Department of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo.
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo.
Chem Pharm Bull (Tokyo). 2023;71(7):584-615. doi: 10.1248/cpb.c23-00250.
Our group has reported various derivatives of lysophosphatidylserine (LysoPS) as potent and subtype-selective agonists for G-protein-coupled receptors (GPCRs). However, the ester linkage between the glycerol moiety and fatty acid or fatty acid surrogate is present in all of them. In order to develop these LysoPS analogs as drug candidates, appropriate pharmacokinetic consideration is essential. Here, we found that the ester bond of LysoPS is highly susceptible to metabolic degradation in mouse blood. Accordingly, we examined isosteric replacement of the ester linkage with heteroaromatic rings. The resulting compounds showed excellent retention of potency and receptor subtype selectivity, as well as increased metabolic stability in vitro.
我们的团队已经报道了各种溶血磷脂酰丝氨酸（LysoPS）衍生物，它们是 G 蛋白偶联受体（GPCR）的有效且亚型选择性激动剂。然而，甘油部分和脂肪酸或脂肪酸类似物之间的酯键存在于所有这些衍生物中。为了将这些 LysoPS 类似物开发为候选药物，适当的药代动力学考虑是必不可少的。在这里，我们发现 LysoPS 的酯键在小鼠血液中极易发生代谢降解。因此，我们检查了用杂环芳烃替代酯键的同系物替换。得到的化合物表现出优异的效力和受体亚型选择性保留，以及体外代谢稳定性提高。
