Inhibition of Sphingosine-1-Phosphate Lyase for the Treatment of Autoimmune Disorders
Inhibition of Sphingosine-1-Phosphate Lyase for the Treatment of Autoimmune Disorders
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DOI：
10.1021/jm900278w
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发表时间：
2009-07-09
影响因子：
7.3
通讯作者：
Augeri, David J.
中科院分区：
文献类型：
--
作者：
Bagdanoff, Jeffrey T.;Donoviel, Michael S.;Augeri, David J.
在近十年的研究致力于研究鞘氨醇信号通路，我们确定鞘氨醇-1-磷酸裂解酶（S1 PL）作为治疗自身免疫性疾病的药物靶标。S1 PL催化鞘氨醇-1-磷酸（S1 P）通过逆向羟醛裂解产生十六烷醛和磷酸乙醇胺的不可逆分解。遗传模型表明，表达降低的S1 PL活性的小鼠由于淋巴细胞运输的改变而减少了循环淋巴细胞的数量，这防止了多种自身免疫性疾病模型中的疾病发展。口服施用2-乙酰基-4（5）-（1（R），2（S），3（R），4-四羟基丁基）-咪唑（THI）3后淋巴组织的机制研究显示了裂解酶活性降低、S1 P水平升高和循环淋巴细胞水平降低之间的明确关系。我们的内部药物化学工作发现了3个带有杂环的有效类似物作为母体结构中存在的侧羰基的化学等价物。通过口服这些类似物减少S1 PL活性概括了具有遗传减少的S1 PL表达的小鼠的表型。
During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S I P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.