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J Med Chem. 2017 Jul 13;60(13):5267-5289. doi: 10.1021/acs.jmedchem.6b01575. Epub 2017 Mar 30.

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P1) Agonists and Future Perspectives.

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1
Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.

Abstract

The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the various proteins involved in the interconversion of the ligands, or targeting the receptors that respond to the ligands. The focus of this article is on the most advanced of the sphingosine-related therapeutics, agonists of sphingosine-1-phosphate receptor 1 (S1P1). The diverse structural classes of S1P1 agonists will be discussed and the status of compounds of clinical relevance will be detailed. An examination of how potential safety concerns are being navigated with compounds currently under clinical evaluation is followed by a discussion of the novel methods being explored to identify next-generation S1P1 agonists with improved safety profiles. Finally, therapeutic opportunities for sphingosine-related targets outside of S1P1 are touched upon.

PMID:
28291340
DOI:
10.1021/acs.jmedchem.6b01575
[Indexed for MEDLINE]

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