TY  - JOUR
A1  - Imeri, Faik
A1  - Fallegger, Daniel
A1  - Zivkovic, Aleksandra
A1  - Schwalm, Stephanie
A1  - Enzmann, Gaby
A1  - Blankenbach, Kira
A1  - Heringdorf, Dagmar Meyer Zu
A1  - Homann, Thomas
A1  - Kleuser, Burkhard
A1  - Pfeilschifter, Josef
A1  - Engelhardt, Britta
A1  - Stark, Holger
A1  - Huwiler, Andrea
T1  - Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice
JF  - Neuropharmacology
N2  - 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 S1P(1) and S1P(3), but not S1P(2), 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 TNF alpha-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNF alpha-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. (C) 2014 Elsevier Ltd. All rights reserved.
KW  - Fingolimod
KW  - ST-968
KW  - ST-1071
KW  - Sphingosine 1-phosphate
KW  - Endothelial cells
KW  - Permeability
KW  - Multiple sclerosis
Y1  - 2014
U6  - https://doi.org/10.1016/j.neuropharm.2014.05.012
SN  - 0028-3908
SN  - 1873-7064
VL  - 85
SP  - 314
EP  - 327
PB  - Elsevier
CY  - Oxford
ER  -