ASP4058, a Novel Agonist for Sphingosine 1-Phosphate Receptors 1 and 5, Ameliorates Rodent Experimental Autoimmune Encephalomyelitis with a Favorable Safety Profile

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of five G protein-coupled receptors (S1P1–S1P5). S1P1 is a major regulator of lymphocyte trafficking, and fingolimod, whose active metabolite fingolimod phosphate acts as a nonselective S1P receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating the lymphocyte trafficking by inducing down regulation of lymphocyte S1P1. Here, we detail the pharmacological profile of 5-{5-[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (ASP4058), a novel next-generation S1P receptor agonist selective for S1P1 and S1P5. ASP4058 preferentially activates S1P1 and S1P5 compared with S1P2, 3, 4 in GTPγS binding assays in vitro. Oral administration of ASP4058 reduced the number of peripheral lymphocytes and inhibited the development of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Further, ASP4058 prevented relapse of disease in a mouse model of relapsing-remitting EAE. Although these immunomodulatory effects were comparable to those of fingolimod, ASP4058 showed a wider safety margin than fingolimod for bradycardia and bronchoconstriction in rodents. These observations suggest that ASP4058 represents a new therapeutic option for treating multiple sclerosis that is safer than nonselective S1P receptor agonists such as fingolimod.

鞘氨醇-1-磷酸（Sphingosine-1-phosphate, S1P）是一类具有生物活性的鞘脂类物质，通过由5种G蛋白偶联受体（G protein-coupled receptors）组成的受体家族成员发挥生物学作用。S1P₁是淋巴细胞迁移的主要调控因子；芬戈莫德（fingolimod）的活性代谢产物芬戈莫德磷酸酯为非选择性S1P受体激动剂，其至少可通过诱导淋巴细胞表面S1P₁的表达下调，调控淋巴细胞迁移，从而发挥免疫调节作用。
本文详细阐述了5-{5-[3-(三氟甲基)-4-{[(2S)-1,1,1-三氟丙-2-基]氧基}苯基]-1,2,4-恶二唑-3-基}-1H-苯并咪唑（ASP4058）的药理学特征，这是一种新型下一代S1P受体选择性激动剂，对S1P₁与S1P₅具有选择性。体外GTPγS结合实验结果显示，相较于S1P₂、S1P₃、S1P₄，ASP4058可优先激活S1P₁和S1P₅。对Lewis大鼠口服给予ASP4058后，其外周淋巴细胞数量显著减少，且可抑制实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis, EAE）的疾病进展。此外，ASP4058可在复发-缓解型EAE小鼠模型中阻断疾病复发。
尽管该药物的免疫调节效果与芬戈莫德相当，但ASP4058在啮齿类动物中展现出比芬戈莫德更宽的心动过缓与支气管收缩安全边际。上述研究结果表明，相较于芬戈莫德这类非选择性S1P受体激动剂，ASP4058是一种更为安全的多发性硬化症（multiple sclerosis）治疗新选择。