期刊论文详细信息
NEUROPHARMACOLOGY 卷:186
Novel compounds with dual S1P receptor agonist and histamine H3 receptor antaglonist activities act protective in a mouse model of multiple sclerosis
Article
Imeri, Faik1  Tanturovska, Bisera Stepanovska1  Zivkovic, Aleksandra2  Enzmann, Gaby3  Schwalm, Stephanie4  Pfeilschifter, Josef4  Homann, Thomas5  Kleuser, Burkhard6  Engelhardt, Britta3  Stark, Holger2  Huwiler, Andrea1 
[1] Univ Bern, Inst Pharmacol, Inselspital INO F, CH-3010 Bern, Switzerland
[2] Heinrich Heine Univ Dusseldorf, Inst Pharmaceut & Med Chem, Univ Str 1, D-40225 Dusseldorf, Germany
[3] Univ Bern, Theodor Kocher Inst, Freiestr 1, CH-3012 Bern, Switzerland
[4] Goethe Univ Frankfurt, Univ Hosp, Pharmazentrum Frankfurt, ZAFES, Theodor Stern Kai 7, D-60590 Frankfurt, Germany
[5] Univ Potsdam, Inst Nutrit Sci, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany
[6] Free Univ Berlin, Dept Pharmacol & Toxicol, Inst Pharm, Konigin Luise Str 2 4, D-14195 Berlin, Germany
关键词: ST-1505;    ST-1478;    Sphingosine 1-phosphate;    Pitolisant;    Histamine;    H3R;    EAE;    Multiple sclerosis;   
DOI  :  10.1016/j.neuropharm.2021.108464
来源: Elsevier
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【 摘 要 】

The sphingosine 1-phosphate (S1P) receptor 1 (S1P(1)) has emerged as a therapeutic target for the treatment of multiple sclerosis (MS). Fingolimod (FTY720) is the first functional antagonist of S1P(1) that has been approved for oral treatment of MS. Previously, we have developed novel butterfly derivatives of FTY720 that acted similar to FTY720 in reducing disease symptoms in a mouse model of experimental autoimmune encephalomyelitis (EAE). In this study, we have synthesized a piperidine derivative of the oxazolo-oxazole compounds, denoted ST-1505, and its ring-opened analogue ST-1478, and characterised their in-vitro and in-vivo functions. Notably, the 3-piperidinopropyloxy moiety resembles a structural motif of pitolisant, a drug with histamine H3R antagonistic/inverse agonist activity approved for the treatment of narcolepsy. Both novel compounds exerted H3R affinities, and in addition, ST-1505 was characterised as a dual S1P(1+3) agonist, whereas ST-1478 was a dual S1P(1+5) agonist. Both multitargeting compounds were also active in mice and reduced the lymphocyte numbers as well as diminished disease symptoms in the mouse model of MS. The effect of ST-1478 was dependent on SK-2 activity suggesting that it is a prodrug like FTY720, but with a more selective S1P receptor activation profile, whereas ST-1505 is a fully active drug even in the absence of SK-2. In summary, these data suggest that the well soluble piperidine derivatives ST-1505 and ST-1478 hold promise as novel drugs for the treatment of MS and other autoimmune or inflammatory diseases, and by their H3R antagonist potency, they might additionally improve cognitive impairment during disease.

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