Discovery of a 1-Methyl-3,4-dihydronaphthalene-Based Sphingosine-1-Phosphate (S1P) Receptor Agonist Ceralifimod (ONO-4641). A S1P₁ and S1P₅ Selective Agonist for the Treatment of Autoimmune Diseases

Abstract

The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P 1 and S1P 5, is described. While it has been revealed that the modulation of the S1P 1 receptor is an effective way to treat autoimmune diseases such as relapsing–remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P 3 receptor is implicated in some undesirable effects. We carried out a structure–activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P 1 over S1P 3 and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED 50 = 0.029 mg/kg, 24 h after oral dosing).