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Abstract
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®), which acts as a functional S1P1 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 S1P1 activation profile and a sustained S1P1 internalization in cultures of S1P1-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 S1P1-selective compounds may have an advantage over fingolimod and siponimod, not only in MS but also in other autoimmune diseases.
Highlights
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, autoimmune disease of the central nervous system (CNS), which affects more than 2.3 million people worldwide, mostly young adults
We present two novel compounds derived from fingolimod, ST-1893 and ST-1894, which chemically feature slight alterations in the polar head group by introducing a substituted
The number of lymphocytes in peripheral blood after 24 h was similar between the groups, with a tendency of decrease by ST-1894, not significant (Figure 9)
Summary
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, autoimmune disease of the central nervous system (CNS), which affects more than 2.3 million people worldwide, mostly young adults. The data obtained from healthy mice, where the depletion of blood lymphocytes was apparent and statistically significant We attribute this discrepancy to the already low level of lymphocytes in the control group, which is in agreement with previous studies and the fact that the development of EAE Int. iJt. sMeollf. The number of lymphocytes in peripheral blood after 24 h was similar between the groups, with a tendency of decrease by ST-1894, not significant (Figure 9) These data support the modeling study confirming that the phosphorylated structures are more potent. T-1893 and ST-1894, whichIpnossusmesms aarys,ehleecrtei,vwe eS1pPre1saenctivtwatoionnovperlosfitrlue.ctBuoretshdceormivpedoufrnodms fainregofulinmcotdio,nSaTl-1a8n9t3agaonndiSstTs- that in1d8u9c4e, wsuhsitcahinpeodssSes1sPa1 isnetleecrtnivaelizSa1tPio nacitnivcaetilol ncuplrtoufrielea. nBdotha pcoromfpoouunnddlsyamrephfuonpcetinoinaailnanmtaicgeo.nAisststhey detmhaotninstdruacteedsuinstvaiinveodeSffi1cPa1ciyntienrnthaleizEaAtioEnminodceelll, caunldtudreueantod tahepirroSfo1uPn1d-selylemctpihvoepneantiuarein, wmeicsep. eAcsulate thtahtetyhedyemwoinllsetrxahteibditinfevwiveor aedffvicearcsye ienffethcetsEaAnEd hmaovdeela,nanaddvdaunetatgoethoevierrSfi1nPg1-oselilmecotidveannadtusirpe,owniemod, nostpoecnulylaitne tMhaSt bthuetyalwsoillinexohthibeirt afeuwtoeirmamdvuenrseedeifsfeeacstsesa.nd have an advantage over fingolimod and siponimod, in MS and in other autoimmune diseases
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