The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: recent findings and new perspectives.

Huwiler, Andrea; Zangemeister-Wittke, Uwe (2018). The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: recent findings and new perspectives. Pharmacology & therapeutics, 185, pp. 34-49. Elsevier 10.1016/j.pharmthera.2017.11.001

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The immunomodulatory drug fingolimod (FTY720, Gilenya(R)) was approved for oral treatment of relapsing-remitting multiple sclerosis, due to its impressive efficacy and good tolerability. Pharmacologically, it acts as an unselective agonist of sphingosine 1-phosphate receptors (S1PR) and as a selective functional antagonist of the S1P1 subtype by induction of receptor downregulation. Since S1P1 is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation and hence immunosuppression. Numerous preclinical studies have since been performed with the aim to increase the spectrum of potential indications for fingolimod with emphasis on other autoimmune disorders and diseases associated with inflammation and uncontrolled cell proliferation, including cancer. As an alternative to fingolimod, novel S1PR modulators with a more selective receptor activation profile and improved pharmacokinetic performance and tolerability have also been developed. Preclinical and clinical studies are ongoing to investigate their therapeutic potential for various indications. This review discusses the most relevant preclinical and clinical findings from S1PR-targeting and from less-well defined off-target effects reported in the literature, and reveals perspectives for using fingolimod and functionally-related derivatives and new formulations in the management of an increasing number of diseases.

Item Type:

Journal Article (Review Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Huwiler, Andrea and Zangemeister-Wittke, Uwe

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0163-7258

Publisher:

Elsevier

Language:

English

Submitter:

Jana Berger

Date Deposited:

14 Dec 2017 15:39

Last Modified:

23 Oct 2019 13:38

Publisher DOI:

10.1016/j.pharmthera.2017.11.001

PubMed ID:

29127024

Uncontrolled Keywords:

Fingolimod S1P receptor modulators adverse events clinical indications pharmacology preclinical developments

BORIS DOI:

10.7892/boris.107169

URI:

https://boris.unibe.ch/id/eprint/107169

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