title: Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice.
abstract: The immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P1 and S1P3, but not S1P2, receptor internalization as a result of receptor activation. Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNFα-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNFα-mediated downregulation of PECAM-1 mRNA expression. In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes and significantly reduced the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice comparable to FTY720 either by prophylactic or therapeutic treatment. In parallel to the reduced clinical symptoms, infiltration of immune cells in the brain was strongly reduced, and in isolated tissues of brain and spinal cord, the mRNA and protein expressions of ICAM-1 and VCAM-1, as well as of matrix metalloproteinase-9 were reduced by all compounds, whereas PECAM-1 and tissue inhibitor of metalloproteinase TIMP-1 were upregulated. In summary, the data suggest that these novel butterfly derivatives of FTY720 could have considerable implication for future therapies of multiple sclerosis and other autoimmune diseases.
authors.affiliation: Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
authors.forename: Faik
authors.initials: F
authors.lastname: Imeri
authors.affiliation: Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fallegger
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Zivkovic
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schwalm
authors.affiliation: Theodor-Kocher Institute, University of Bern, Freiestrasse 1, CH-3012 Bern, Switzerland.
authors.forename: Gaby
authors.initials: G
authors.lastname: Enzmann
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Kira
authors.initials: K
authors.lastname: Blankenbach
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Meyer zu Heringdorf
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Homann
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.affiliation: Theodor-Kocher Institute, University of Bern, Freiestrasse 1, CH-3012 Bern, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland; Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. Electronic address: Huwiler@pki.unibe.ch.
authors.forename: Andrea
authors.initials: A
authors.lastname: Huwiler
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D003412:Cricetulus; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D011409:Propylene Glycols / Q000737:chemistry / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D020298:U937 Cells
chemical_list: C000596159:7a-(4-(heptyloxy)phenethyl)tetrahydro-1H-oxazolo(3,4-c)oxazole; C000596158:7a-(4-octylphenethyl)tetrahydro-1H-oxazolo(3,4-c)oxazole; D007166:Immunosuppressive Agents; D010080:Oxazoles; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: Endothelial cells; Fingolimod; Multiple sclerosis; Permeability; ST-1071; ST-968; Sphingosine 1-phosphate