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

Abstract

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.

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