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 S1P₁ and S1P₅, is described. While it has been revealed that the modulation of the S1P₁ receptor is an effective way to treat autoimmune diseases such as relapsing–remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P₃ 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 S1P₁ over S1P₃ and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED₅₀ = 0.029 mg/kg, 24 h after oral dosing).

中文翻译：

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发现基于1-甲基-3,4-二氢萘的Sphingosine-1-磷酸盐（S1P）受体激动剂Ceralifimod（ONO-4641）。S1P ₁和S1P ₅选择性激动剂，用于治疗自身免疫性疾病

1-（{6-[（2-甲氧基-4-丙基苄基）氧基] -1-甲基-3,4-二氢萘-2-基}甲基）氮杂环丁烷-3-羧酸13n（ceralifimod，ONO- （4641），描述了对S1P ₁和S1P ₅具有选择性的鞘氨醇-1-磷酸（S1P）受体激动剂。尽管已经发现调节S1P ₁受体是治疗自身免疫性疾病（例如复发-缓解型多发性硬化症（RRMS））的有效方法，但也有报道称S1P ₃受体的激活与某些不良作用有关。我们对命中化合物6进行了结构-活性关系（SAR）研究在亲水性头部区域具有氨基酸部分。在通过诱导构象约束力鉴定具有二氢萘中心核的先导化合物之后，亲脂性尾部区域的优化导致发现13n作为临床候选物，其对S1P _1的选择性比S1P _3高> 30 000倍，并且在小鼠外周淋巴细胞降低（PLL）测试（口服给药24小时后，ED ₅₀ = 0.029 mg / kg）。