TY  - JOUR
A1  - Stepanovska, Bisera
A1  - Zivkovic, Aleksandra
A1  - Enzmann, Gaby
A1  - Tietz, Silvia
A1  - Homann, Thomas
A1  - Kleuser, Burkhard
A1  - Engelhardt, Britta
A1  - Stark, Holger
A1  - Huwiler, Andrea
T1  - Morpholino analogues of fingolimod as novel and selective S1P1 ligands with in vivo efficacy in a mouse model of experimental antigen-induced encephalomyelitis
JF  - International journal of molecular sciences
N2  - Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system (CNS) which is associated with lower life expectancy and disability. The experimental antigen-induced encephalomyelitis (EAE) in mice is a useful animal model of MS, which allows exploring the etiopathogenetic mechanisms and testing novel potential therapeutic drugs. A new therapeutic paradigm for the treatment of MS was introduced in 2010 through the sphingosine 1-phosphate (S1P) analogue fingolimod (FTY720, Gilenya(R)), which acts as a functional S1P(1) antagonist on T lymphocytes to deplete these cells from the blood. In this study, we synthesized two novel structures, ST-1893 and ST-1894, which are derived from fingolimod and chemically feature a morpholine ring in the polar head group. These compounds showed a selective S1P(1) activation profile and a sustained S1P(1) internalization in cultures of S1P(1)-overexpressing Chinese hamster ovary (CHO)-K1 cells, consistent with a functional antagonism. In vivo, both compounds induced a profound lymphopenia in mice. Finally, these substances showed efficacy in the EAE model, where they reduced clinical symptoms of the disease, and, on the molecular level, they reduced the T-cell infiltration and several inflammatory mediators in the brain and spinal cord. In summary, these data suggest that S1P(1)-selective compounds may have an advantage over fingolimod and siponimod, not only in MS but also in other autoimmune diseases.
KW  - ST-1893
KW  - ST-1894
KW  - morpholino analogues of fingolimod
KW  - sphingosine
KW  - 1-phosphate
KW  - immunomodulator
KW  - lymphopenia
KW  - multiple sclerosis
KW  - experimental antigen-induced encephalomyelitis
Y1  - 2020
U6  - https://doi.org/10.3390/ijms21186463
SN  - 1422-0067
VL  - 21
IS  - 18
PB  - MDPI
CY  - Basel
ER  -