ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo.

Bisera Stepanovska Tanturovska,Thomas Homann,Faik Imeri,Holger Stark,Aleksandra Zivkovic,Burkhard Kleuser,Andrea Huwiler

doi:10.3390/molecules26175134

Abstract

Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P concentrations are low drives T cell trafficking. S1P1 modulators, such as fingolimod, disrupt this recycling by inducing persistent S1P1 internalization and receptor degradation, which results in blocked egress of T cells from the secondary lymphoid tissues. The approval of these compounds for the treatment of multiple sclerosis has placed the development of S1PR modulators in the focus of pharmacological research, mostly for autoimmune indications. Here, we report on a novel anellated bismorpholino derivative of oxy-fingolimod, named ST-2191, which exerts selective S1P1 agonist and functional antagonist potency. ST-2191 is also effective in reducing the lymphocyte number in mice, and this effect is not dependent on phosphorylation by sphingosine kinase 2 for activity. These data show that ST-2191 is a novel S1P1 modulator, but further experiments are needed to analyze the therapeutic impact of ST-2191 in animal models of autoimmune diseases.

Highlights

Based on the LIPID MAPS classification system, sphingolipids represent one out of the eight categories of lipids [1,2]
DInistchuissssitoundy, using oxy-fingolimod as a precursor, we synthesized ST-2191, a novel compoIunntdhiws sithudayn, uisnitnegreosxtiyn-gfinngeowlimanoedllasteadpbreiscmurosroprh, woliensoynmthoeiestiyz.edThSTis-2c1o9m1,paounonvdel compound with an interesting new anellated bismorpholino moiety. This compound showed a selective S1P1 agonistic and functional antagonistic activation profile and reduced the lymphocyte number in mice, demonstrating an immunomodulatory effect that is desired for the treatment of various autoimmune and inflammatory diseases [5]
ST-2191 can be synthesized in an analogous route to that of ST-1894, a previously reported S1P1 receptor modulator with a morpholino moiety (Figure 1) [18]

Summary

Introduction

Based on the LIPID MAPS classification system, sphingolipids represent one out of the eight categories of lipids [1,2] They are increasingly recognized as structural components of biological membranes but as bioactive molecules regulating multiple physiological and pathophysiological processes. The first step in these cellular responses is the binding of S1P to specific high-affinity cell surface receptors (S1PRs), of which five subtypes have been described, named S1P1, S1P2, S1P3, S1P4 and S1P5 [4,5]. These receptors belong to the superfamily of G-protein coupled receptors (GPCR). The concentration of S1P in various body compartments, such as blood or secondary lymphoid organs, varies drastically, which may even trigger opposite reactions by the same cells

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Conclusion