Abstract
Compound 1 (FTY720, Fingolimod) represents a new generation of immunosuppressant that modulates lymphocyte trafficking by interacting with the S1P(1) receptor. Compound 1 also provides a template molecule for studying the molecular biology of S1P receptors and related enzymes (kinases and phosphatases). In this study, two conformationally constrained analogues of 1 ( 3a and 3c) were asymmetrically synthesized in high optical purity. In vitro assessment documented that both analogues are Sphk2 substrates, their phosphorylated species are potent S1P(1) receptor agonists, and 3a-P is a potent S1P 3 antagonist. After oral administration in mice, both compounds evoked lymphopenia, but their duration of action differed markedly.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Calcium / metabolism
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Cell Line
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Cricetinae
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Cricetulus
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Fingolimod Hydrochloride
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Humans
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Immunologic Factors / chemical synthesis*
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Immunologic Factors / chemistry
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Immunologic Factors / pharmacology
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Mice
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Phosphorylation
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Prodrugs / chemical synthesis*
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Prodrugs / chemistry
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Prodrugs / pharmacology
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Propylene Glycols / chemical synthesis*
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Propylene Glycols / chemistry
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Propylene Glycols / pharmacology
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Radioligand Assay
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Receptors, Lysosphingolipid / agonists*
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Receptors, Lysosphingolipid / antagonists & inhibitors*
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Sphingosine / analogs & derivatives*
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Sphingosine / chemical synthesis
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Sphingosine / chemistry
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Sphingosine / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Immunologic Factors
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Prodrugs
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Propylene Glycols
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Receptors, Lysosphingolipid
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Fingolimod Hydrochloride
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Sphingosine
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Calcium