Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates a variety of physiological processes including lymphocyte recirculation and cardiac function. Most S1P effects are mediated via five G-protein-coupled S1P receptor subtypes referred to as S1P1–5 (originally termed EDG-1, 3, 5, 6, and 8)
[7][1]. These receptors are differentially expressed on various cell types, including lymphocytes
[8,9][2][3], cardiomyocytes
[10,11][4][5] and brain cells. In 2000, Kuppermann showed that S1P receptors regulate cell migration during vertebrate heart development
[12][6], and two years later a similar pro-migratory effect of S1P receptors was demonstrated for CD4
+ T cells
[13][7]. Two years after, in 2004, Matloubian for the first time showed that the egress of lymphocytes from the thymus and the peripheral lymphoid organs is dependent on S1P1
[14][8]. Due to these observations, the anti-inflammatory potency of S1P-receptor modulators have been intensively investigated.
The S1P-receptor modulator fingolimod, also called FTY720, induces a rapid and drastic deletion of T cells from the peripheral blood by inhibiting the egress of T cells from the thymus
[15][9] and lymph nodes. By this mechanism, fingolimod prevents the entry of lymphocytes into the blood, and thus T cell infiltration into the CNS
[16,17,18][10][11][12]. It has additionally been demonstrated that fingolimod can trigger lymphocyte apoptosis
[16,19,20][10][13][14]. Consequently, preclinical studies show that fingolimod ameliorates pathology in several models of autoimmune diseases, including type 1 diabetes
[21][15], adjuvant-induced arthritis
[22][16], systemic lupus erythematosus
[23][17] and, most importantly in the context of MS research, in different models of experimental autoimmune encephalomyelitis (EAE)
[24,25][18][19]. In a number of clinical trials, it has been shown that fingolimod is well tolerated and associated with low relapse rates and lesion activity in relapsing-remitting MS patients
[26,27,28,29][20][21][22][23]. Consequently, fingolimod was the first oral disease-modifying therapeutic agent to be approved for the treatment of MS. This pro-drug is rapidly converted in vivo into the active S-fingolimod-phosphate (FTY720-P) which is a potent agonist on S1P1, S1P3, S1P4 and S1P5 receptors. Since S1P-receptors are ubiquitinated and subsequently degraded when exposed to FTY720-P
[30][24], the experimental and clinical efficacy of FTY720-P is thought to involve functional antagonism by persistent internalization and enhanced degradation of the S1P-receptor. Of note, its efficacy in MS and related animal models may in part be due to additional, direct effects within the brain. For example, a strong increase in S1P1 and S1P3 expression on reactive astrocytes was detected in active and chronic inactive MS lesions
[31][25], whereas another study has suggested S1P5 expression in oligodendrocytes
[32,33][26][27].
In general, fingolimod has a favorable benefit-risk profile
[56][28]. However, a critical challenge of fingolimod therapy still remains in the initiation phases due to the risk of cardiac events. The first dose of fingolimod is associated with a decrease in heart rate and slowing of atrioventricular conduction
[28,29,57][22][23][29]. The discovery of the S1P3 receptor mediating bradycardia in mice
[58][30] prompted the search for S1P-receptor modulators devoid of S1P3 signaling. This effort led to the discovery of siponimod (also called BAF312), which is a selective modulator of S1P1 and S1P5 receptors. Siponimod was furthermore designed to have a relatively short elimination half-life that provides a rapid recovery of blood lymphocyte counts on stopping treatment, but would allow once-daily oral dosing
[59][31].