Cyrille Lescop

Synthetic sphingosine 1-phosphate receptor modulators--opportunities and potential pitfalls.

Sphingosine 1-phosphate (S1P) evokes a plethora of physiological responses by stimulating members of a G protein-coupled receptor family, known as S1P receptors. Currently five different mammalian S1P receptor subtypes, S1P₁₋₅, each with a different cellular expression pattern, were identified. The S1P₁ receptor in particular has attracted major interest throughout the pharmaceutical industry following the breakthrough discovery that this S1P receptor subtype is critically involved in the regulation of lymphocyte trafficking through secondary lymphoid organs. Since then, examples of synthetic S1P₁ agonists with lymphocyte reducing and immunomodulating activity demonstrated efficacy in numerous preclinical models of autoimmune disease and transplantation. Notably FTY720 (fingolimod), a pro-drug that is phosphorylated in vivo and converted into a non-selective S1P₁,₃,₄,₅ receptor agonist, has been widely used to increase the understanding of S1P₁ receptor biology. Results from recently completed phase III clinical trials using FTY720 paved the way for this non-selective S1P₁ receptor agonist to become the first oral therapy in multiple sclerosis, with potential expansion into many other autoimmune diseases. This review briefly outlines the field of S1P₁ receptor biology and summarizes recent approaches in medicinal chemistry to discover potent and selective S1P₁ receptor agonists. In particular, the complexity of discovering a molecule akin to FTY720 but with an improved side-effect profile will be discussed.

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

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 S1P1‐5 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.

S1P1 modulator-induced Gαi Signaling and β-Arrestin Recruitment Are Both Necessary to Induce Rapid and Efficient Reduction of Blood Lymphocyte Count in vivo

S1P1 (sphingosine-1-phosphate receptor 1) agonists prevent lymphocyte egress from secondary lymphoid organs and cause a reduction in the number of circulating blood lymphocytes. We hypothesized that S1P1 receptor modulators with pathway-selective signaling properties could help to further elucidate the molecular mechanisms involved in lymphocyte trapping. A proprietary S1P1 receptor modulator library was screened for compounds with clear potency differences in β-arrestin recruitment and G protein alpha i subunit (Gαi) protein-mediated signaling. We describe here the structure-activity relationships of highly potent S1P1 modulators with apparent pathway selectivity for β-arrestin recruitment. The most differentiated compound, D3-2, displayed a 180-fold higher potency in the β-arrestin recruitment assay (EC50 0.9 nM) compared with the Gαi-activation assay (167 nM), whereas ponesimod, a S1P1 modulator that is currently in advanced clinical development in multiple sclerosis, was equipotent in both assays (EC50 1.5 and 1.1 nM, respectively). Using these novel compounds as pharmacological tools, we showed that although a high potency in β-arrestin recruitment is required to fully internalize S1P1 receptors, the potency in inducing Gαi signaling determines the rate of receptor internalization in vitro. In contrast to ponesimod, the compound D3-2 did not reduce the number or circulating lymphocytes in rats despite high plasma exposures. Thus, for rapid and maximal S1P1 receptor internalization a high potency in both Gαi signaling and β-arrestin recruitment is mandatory and this translates into efficient reduction of the number of circulating lymphocytes in vivo.