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Updated: Jul 24, 2025

Defining Substrate Specificities for Lipase and Phospholipase Candidates
Published on: November 23, 2016
Isosteric Replacement of Ester Linkage of Lysophospholipids with Heteroaromatic Rings Retains Potency and Subtype
Masaya Ikubo1, Akiharu Uwamizu2, Luying Chen1
1Department of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo.
Abstract:
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.
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