New fluorinated agonists for targeting the sphingosin-1-phosphate receptor 1 (S1P(1))

Rizwan S Shaikh; Petra Keul; Michael Schäfers; Bodo Levkau; Günter Haufe

doi:10.1016/j.bmcl.2015.10.026

New fluorinated agonists for targeting the sphingosin-1-phosphate receptor 1 (S1P(1))

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5048-51. doi: 10.1016/j.bmcl.2015.10.026. Epub 2015 Oct 22.

Authors

Rizwan S Shaikh¹, Petra Keul², Michael Schäfers³, Bodo Levkau², Günter Haufe⁴

Affiliations

¹ Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany; NRW Graduate School of Chemistry, Westfälische Wilhelms-Universität Münster, Wilhelm-Klemm-Straße 10, D-48149 Münster, Germany.
² Institute for Pathophysiology, Westdeutsches Herz- und Gefäßzentrum, University Hospital, Essen, University of Duisburg-Essen, Hufelandstraße 55, D-45122 Essen, Germany.
³ Klinik für Nuklearmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, D-48149 Münster, Germany; European Institute for Molecular Imaging-EIMI, Westfälische Wilhelms-Universität Münster, Waldeyerstraße 15, D-48149 Münster, Germany; Cells-in-Motion Centre of Excellence, Westfälische Wilhelms-Universität Münster, Waldeyerstraße 15, D-48149 Münster, Germany.
⁴ Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany; European Institute for Molecular Imaging-EIMI, Westfälische Wilhelms-Universität Münster, Waldeyerstraße 15, D-48149 Münster, Germany; Cells-in-Motion Centre of Excellence, Westfälische Wilhelms-Universität Münster, Waldeyerstraße 15, D-48149 Münster, Germany.

PMID: 26592813
DOI: 10.1016/j.bmcl.2015.10.026

Abstract

The sphingosine-1-phosphate receptor type 1 (S1P1) is involved in fundamental biological processes such as regulation of immune cell trafficking, vascular barrier function and angiogenesis. This Letter presents multistep syntheses of various fluorine substituted 12-aryl analogues of the drug fingolimod (FTY720) and a seven-steps route to 2-amino-17,17-difluoro-2-(hydroxymethyl)heptadecan-1-ol. In vitro and in vivo tests proved all these compounds as potent S1P1 receptor agonists.

Keywords: FTY720 analogues; Fluorine; G protein-coupled receptors; S1P(1) receptor agonist; Sphingosine-1-phosphate (S1P).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocytes / cytology
B-Lymphocytes / drug effects
CD4 Lymphocyte Count
CD8-Positive T-Lymphocytes / cytology
CD8-Positive T-Lymphocytes / drug effects
CHO Cells
Cricetulus
Fatty Alcohols / chemical synthesis
Fatty Alcohols / pharmacology*
Fingolimod Hydrochloride / pharmacology
Hydrocarbons, Fluorinated / chemical synthesis
Hydrocarbons, Fluorinated / pharmacology*
Immunosuppressive Agents / chemical synthesis
Immunosuppressive Agents / pharmacology*
Mice
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Phosphorylation
Receptors, Lysosphingolipid / agonists*
Sphingosine-1-Phosphate Receptors

Substances

2-amino-17,17-difluoro-2-(hydroxymethyl)heptadecan-1-ol
Fatty Alcohols
Hydrocarbons, Fluorinated
Immunosuppressive Agents
Receptors, Lysosphingolipid
S1PR1 protein, human
Sphingosine-1-Phosphate Receptors
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Fingolimod Hydrochloride