Institut für Chemie, Humboldt Universität zu Berlin, 12489 Berlin, Germany.
Bioorg Med Chem. 2010 Jan 15;18(2):939-44. doi: 10.1016/j.bmc.2009.11.030. Epub 2009 Dec 11.
The acid sphingomyelinase is an emerging drug target, especially for inflammatory lung diseases. Presently, there are no directly-acting potent inhibitors available for cell-based studies. The potent inhibitor phosphatidylinositol-3,5-bisphosphate (PtdIns3,5P2) is not only unsuited for cell culture studies, but also does not provide hints for further structural improvements. In the SAR study described here, we replaced the inositolphosphate moiety by a carbohydrate derivative and the phosphatidic acid residue by an alkylsulfone ester. The resulting compound is more active than its parent compound and offers new means for further structural modification.
酸性鞘磷脂酶是一个新兴的药物靶点，特别是针对炎症性肺病。目前，还没有直接作用的有效抑制剂可用于基于细胞的研究。有效的抑制剂磷脂酰肌醇-3,5-双磷酸（PtdIns3,5P2）不仅不适合细胞培养研究，而且也不能为进一步的结构改进提供线索。在本文描述的 SAR 研究中，我们用碳水化合物衍生物取代了肌醇磷酸盐部分，用烷基砜酯取代了磷脂酸残基。得到的化合物比其母体化合物更具活性，并为进一步的结构修饰提供了新的手段。
