2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1 Receptor Agonists
2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1 Receptor Agonists
复制标题
DOI：
10.1021/jm100181s
复制
发表时间：
2010-05-27
影响因子：
7.3
通讯作者：
Weller, Thomas
中科院分区：
文献类型：
--
作者：
Bolli, Martin H.;Abele, Stefan;Weller, Thomas
鞘氨醇-L-磷酸(S1P)是一种广泛存在的溶血磷脂，具有丰富的生物学效应。胞外S1P通过编号为S1P(1)至S1P(5)的5个特异性G蛋白偶联受体传递其活性。S1P(1)受体激动剂阻止T淋巴细胞从胸腺和淋巴器官流出，有望用于自身免疫性疾病的口服治疗。在这里，我们报道了一类基于2-亚氨基-噻唑烷-4-酮支架的新型S1P(1)受体激动剂的发现和详细的构效关系。化合物8BO(ACT-128800)从该系列中脱颖而出，是一种有效的、选择性的、口服活性的S1P(1)受体激动剂，用于临床开发。在大鼠中，循环淋巴细胞在3 mg/kg剂量时达到最大值。淋巴细胞隔离时间呈剂量依赖关系。在100 mg/kg剂量下，对淋巴细胞计数的影响在不到36h内完全可逆。8bo在Beagle犬体内的药代动力学研究表明，该化合物适合于人每天一次给药。
Sphingosine-l-phosphate (S1P) is a widespread lysophospholipid which displays a wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P(1) through S1P(5). Agonists of the S1P(1) receptor block the egress of T-lymphocytes from thymus and lymphoid organs and hold promise for the oral treatment of autoimmune disorders. Here, we report on the discovery and detailed structure-activity relationships of a novel class of S1P(1) receptor agonists based on the 2-imino-thiazolidin-4-one scaffold. Compound 8bo (ACT-128800) emerged from this series and is a potent, selective, and orally active S1P(1) receptor agonist selected for clinical development. In the rat, maximal reduction of circulating lymphocytes was reached at a dose of 3 mg/kg. The duration of lymphocyte sequestration was dose dependent. At a dose of 100 mg/kg, the effect on lymphocyte counts was fully reversible within less than 36 h. Pharmacokinetic investigation of 8bo in beagle dogs suggests that the compound is suitable for once daily dosing in humans.