Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd.
Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University.
Biol Pharm Bull. 2021;44(2):188-196. doi: 10.1248/bpb.b20-00580.
ONO-4641, 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid (ceralifimod), is a second-generation sphingosine 1-phosphate receptor agonist selective for sphingosine 1-phosphate receptors 1 and 5, and has clinical effects in multiple sclerosis. The objective of the present study was to explore other potential indications for ONO-4641 based on its immunomodulatory effects. ONO-4641 was tested in non-obese diabetic (NOD) mice, an animal model of spontaneous type 1 diabetes mellitus, an autoimmune disease with unmet medical needs. ONO-4641 at a dose of 0.1 mg/kg prevented the onset of diabetes mellitus in NOD mice. Furthermore, ONO-4641 at doses of 0.03 and 0.1 mg/kg decreased diabetic prevalence in NOD mice after the onset of diabetes mellitus in a dose-dependent manner. Histopathological analysis demonstrated that insulin-positive areas in the islets of mice administered 0.03 and 0.1 mg/kg ONO-4641 showed a tendency of high values although they were not significantly different from the Control group, which was treated with vehicle. These observations suggest ONO-4641 may delay the onset and progression of type 1 diabetes mellitus.
ONO-4641，1-({6-[(2-甲氧基-4-丙基苄基)氧基]-1-甲基-3,4-二氢萘-2-基}甲基)氮杂啶-3-羧酸（塞立利姆），是第二代鞘氨醇 1-磷酸受体激动剂，对鞘氨醇 1-磷酸受体 1 和 5 具有选择性，在多发性硬化症中具有临床疗效。本研究的目的是基于其免疫调节作用，探索 ONO-4641 的其他潜在适应症。在非肥胖型糖尿病（NOD）小鼠中测试了 ONO-4641，NOD 小鼠是一种自发性 1 型糖尿病的动物模型，是一种具有未满足医疗需求的自身免疫性疾病。0.1mg/kg 的 ONO-4641 剂量可预防 NOD 小鼠糖尿病的发生。此外，0.03 和 0.1mg/kg 的 ONO-4641 剂量可在糖尿病发病后，以剂量依赖性方式降低 NOD 小鼠的糖尿病患病率。组织病理学分析表明，给予 0.03 和 0.1mg/kg ONO-4641 的小鼠胰岛中胰岛素阳性区域虽然与给予载体的对照组相比没有显著差异，但有较高的趋势。这些观察结果表明，ONO-4641 可能延迟 1 型糖尿病的发生和进展。
