Novel compounds with dual S1P receptor agonist and histamine H3 receptor antagonist activities act protective in a mouse model of multiple sclerosis.

Imeri, Faik; Stepanovska Tanturovska, Bisera; Zivkovic, Aleksandra; Enzmann, Gaby; Schwalm, Stephanie; Pfeilschifter, Josef; Homann, Thomas; Kleuser, Burkhard; Engelhardt, Britta; Stark, Holger; Huwiler, Andrea (2021). Novel compounds with dual S1P receptor agonist and histamine H3 receptor antagonist activities act protective in a mouse model of multiple sclerosis. Neuropharmacology, 186, p. 108464. Elsevier 10.1016/j.neuropharm.2021.108464

[img] Text
Huwiler__Novel_compounds_with_dual_SIP_receptor.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (6MB) | Request a copy

The sphingosine 1-phosphate (S1P) receptor 1 (S1P1) has emerged as a therapeutic target for the treatment of multiple sclerosis (MS). Fingolimod (FTY720) is the first functional antagonist of S1P1 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 S1P1+3 agonist, whereas ST-1478 was a dual S1P1+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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Imeri, Faik, Stepanovska Tanturovska, Bisera, Enzmann, Gaby, Engelhardt, Britta, Huwiler, Andrea


600 Technology > 610 Medicine & health








Celine Joray

Date Deposited:

24 Feb 2021 14:47

Last Modified:

05 Dec 2022 15:48

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

EAE H(3)R Histamine Multiple sclerosis Pitolisant ST-1478 ST-1505 Sphingosine 1-phosphate




Actions (login required)

Edit item Edit item
Provide Feedback