Kurata Haruto, Kusumi Kensuke, Otsuki Kazuhiro, Suzuki Ryo, Kurono Masakuni, Komiya Takaki, Hagiya Hiroshi, Mizuno Hirotaka, Shioya Hiroki, Ono Takeji, Takada Yuka, Maeda Tatsuo, Matsunaga Norikazu, Kondo Tetsu, Tominaga Sachiko, Nunoya Ken-Ici, Kiyoshi Hidekazu, Komeno Masaharu, Nakade Shinji, Habashita Hiromu
Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Safety Research Laboratories, Ono Pharmaceutical Co., Ltd. , 50-10 Yamagishi, Mikuni, Sakai, Fukui 913-8538, Japan.
J Med Chem. 2017 Dec 14;60(23):9508-9530. doi: 10.1021/acs.jmedchem.7b00785. Epub 2017 Nov 21.
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 and S1P, is described. While it has been revealed that the modulation of the S1P 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 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 over S1P and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED = 0.029 mg/kg, 24 h after oral dosing).
描述了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（塞拉利莫德，ONO-4641）的发现，它是一种对S1P₁和S1P₃具有选择性的鞘氨醇-1-磷酸（S1P）受体激动剂。虽然已经揭示S1P受体的调节是治疗诸如复发缓解型多发性硬化症（RRMS）等自身免疫性疾病的有效方法，但也有报道称S1P受体的激活与一些不良影响有关。我们对亲水头区域带有氨基酸部分的命中化合物6进行了构效关系（SAR）研究。通过引入构象限制鉴定出具有二氢萘中心核的先导化合物后，对亲脂性尾部区域进行优化，从而发现了13n作为临床候选药物，其对S1P₁的选择性比对S1P₃高>30000倍，并且在小鼠外周淋巴细胞降低（PLL）试验中具有活性（口服给药24小时后，ED₅₀ = 0.029 mg/kg）。
