A novel series of fingolimod analogues containing diphenyl ether moiety were designed and synthesized based on the modification of immunosuppressive agent fingolimod used in the treatment of multiple sclerosis. Compounds were evaluated in vivo for lymphopenic activity and heart rate affection. Most compounds showed moderate lymphopenic activity. It is worth noting that compounds 6c, 6d and 14c-14e showed considerable immunosuppressive activities comparable to fingolimod. And compound 14e had no effect on heart rate.
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Nat Commun
January 2025
Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count and hearing defects. SPNS2 also exports the S1P-mimicking FTY720-P (Fingolimod) and thereby is central to the pharmacokinetics of this drug when treating multiple sclerosis.
View Article and Find Full Text PDFImmunology
January 2025
Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK.
Inflammatory environments induce the generation of dysfunctional IFNγT-betFOXP3 Th1-like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1-like Tregs are not well understood. Sphingosine-1-phosphate (S1P) signalling molecules are upregulated in Th1-like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients.
View Article and Find Full Text PDFImmunol Lett
December 2024
Lab of Translational ImmunoMedicine (LaTIM), Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea; Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea; Department of Medical Sciences, Graduate School of The Catholic University of Korea, South Korea. Electronic address:
Background: Sjögren's syndrome (SS) is an autoimmune disease caused by infiltrating lymphocytes. FTY720 affects the S1P signaling pathway, which plays a role in T and B cell migration from secondary lymphoid tissues to target organs. In this study, we investigate the regulatory mechanism of FTY720 in the context of SS.
View Article and Find Full Text PDFPflugers Arch
December 2024
Institut für Allgemeine Pharmakologie und Toxikologie, Goethe-Universität Frankfurt Am Main, Theodor-Stern-Kai 7, 60590, Frankfurt Am Main, Germany.
Neuropharmacology
December 2024
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. Electronic address:
Sphingosine-1-phosphate (S1P) receptor (S1PR) agonists, such as fingolimod (FTY720), alleviate nociception in preclinical pain models by either activation (agonism) or inhibition (functional antagonism) of S1PR type-1 (S1PR1). However, the dose-dependence and temporal relationship between reversal of nociception and modulation of S1PR1 signaling has not been systematically investigated. This study examined the relationship between FTY720-induced antinociception and S1PR1 adaptation using a sciatic nerve chronic constriction injury (CCI) model of neuropathic pain in male and female C57Bl/6J mice.
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