Cenerimod, a novel selective S1P1 receptor modulator with unique signaling properties

Abstract

Sphingosine-1-phosphate receptor 1 (S1P₁ ) modulators sequester circulating lymphocytes within lymph nodes, thereby preventing potentially pathogenic autoimmune cells from exiting into the blood stream and reaching inflamed tissues. S1P₁ receptor modulation may thus offer potential to treat various autoimmune diseases. The first nonselective S1P_1-5 receptor modulator FTY720/fingolimod/Gilenya^® has successfully demonstrated clinical efficacy in relapsing forms of multiple sclerosis. However, cardiovascular, hepatic, and respiratory side-effects were reported and there is a need for novel S1P₁ receptor modulators with better safety profiles. Here, we describe the discovery of cenerimod, a novel, potent and selective S1P₁ receptor modulator with unique S1P₁ receptor signaling properties and absence of broncho- and vasoconstrictor effects ex vivo and in vivo. Cenerimod dose-dependently lowered circulating lymphocyte counts in rats and mice after oral administration and effectively attenuated disease parameters in a mouse experimental autoimmune encephalitis (EAE) model. Cenerimod has potential as novel therapy with improved safety profile for autoimmune diseases with high unmet medical need.

Keywords: G protein-coupled receptor signaling; autoimmune diseases; lipid receptors; lymphocyte trafficking; multiple sclerosis; sphingosine-1-phosphate.