Synthesis of new ligands for targeting the S1P1 receptor

A series of fluorinated sphingosine derivatives including aliphatic FTY720 analogues have been tested as S1P1 receptor agonists. Bioisosteric replacement of the 3-OH group by fluorine or attachment of this substituent in the proximity of the crucial 2-amino-1,3-diol moiety resulted in drop of potenc...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2015-03, Vol.23 (5), p.1011-1026
Main Authors: Schilson, Stefanie S., Keul, Petra, Shaikh, Rizwan S., Schäfers, Michael, Levkau, Bodo, Haufe, Günter
Format: Article
Language:English
Subjects:
Animals
CHO Cells
Cricetinae
Cricetulus
Fingolimod Hydrochloride - chemical synthesis
Fingolimod Hydrochloride - chemistry
Fingolimod Hydrochloride - pharmacology
Fluorine
FTY720 analogues
G protein-coupled receptors
Humans
Immunosuppressive Agents - chemical synthesis
Immunosuppressive Agents - chemistry
Immunosuppressive Agents - pharmacology
Ligands
Mice
Receptors, Lysosphingolipid - drug effects
Receptors, Lysosphingolipid - metabolism
S1P1 receptor agonists
Sphingosine-1-phosphate (S1P)
Structure–activity relationship
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Summary:A series of fluorinated sphingosine derivatives including aliphatic FTY720 analogues have been tested as S1P1 receptor agonists. Bioisosteric replacement of the 3-OH group by fluorine or attachment of this substituent in the proximity of the crucial 2-amino-1,3-diol moiety resulted in drop of potency, while ω-fluorinated analogues were equally potent as their parent hydrocarbons. [Display omitted] Sphingosine-1-phosphate (S1P) influences various fundamental biological processes by interacting with a family of five G protein-coupled receptors (S1P1–5). FTY720, a sphingosine analogue, which was approved for treatment of relapsing forms of multiple sclerosis, is phosphorylated in vivo and acts as an agonist of four of the five S1P receptor subtypes. Starting from these lead structures we developed new agonists for the S1P1 receptor. The biological activity was tested in vivo and promising ligands were fluorinated at different positions to identify candidates for positron emission tomography (PET) imaging after [18F]-labelling. The radioligands shall enable the imaging of S1P1 receptor expression in vivo and thus may serve as novel imaging markers of S1P-related diseases.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2015.01.014