Abe A, Wild S R, Lee W L, Shayman J A
University of Michigan Medical Center, Department of Internal Medicine, Ann Arbor 48109-0676, USA.
Curr Drug Metab. 2001 Sep;2(3):331-8. doi: 10.2174/1389200013338414.
We have developed a series of inhibitors of glucosylceramide synthase that are structurally based on the parent compound D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). These inhibitors provide useful tools for manipulating glycosphingolipid levels in cells and for elucidating questions associated with sphingolipid signaling. Recently, two highly active glucosylceramide synthase inhibitors, D-threo-3', 4'-ethylenedioxy-1-phenyl-2-palmitoylamino-3- pyrrolidino-1-propanol and D-threo-4'-hydroxy-1-phenyl-2-palmitoylamino-3- pyrrolidino-1-propanol, were designed, synthesized, and studied. These inhibitors markedly reduced glycosphingolipid levels in MDCK cells without any accumulation of intracellular ceramide and associated growth inhibition. Subsequently, each inhibitor was evaluated for its ability to lower glycolipid levels in virally transformed lymphoblasts from a patient with alpha-galactosidase A deficiency. Both compounds significantly reduced neutral glycosphingolipid levels in the lymphoblasts without any morphological changes and growth inhibition. Furthermore, the inhibitors were applied to a mouse knockout model of Fabry disease. Inhibitor treatment blocked accumulation of globotriaosylceramide (Gb3) in the kidney, liver and heart of mice. In contrast to another glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, this treatment was not associated with any significant change in body weight or organ weight and without immunodepletion. These results suggest that these newest PDMP homologues are promising as therapeutic agents for the treatment of glycosphingolipid storage disorders.
我们已经开发出一系列基于母体化合物D-苏式-1-苯基-2-癸酰氨基-3-吗啉代-1-丙醇（PDMP）的葡萄糖神经酰胺合酶抑制剂。这些抑制剂为调控细胞中糖鞘脂水平以及阐明与鞘脂信号传导相关的问题提供了有用的工具。最近，设计、合成并研究了两种高活性的葡萄糖神经酰胺合酶抑制剂，即D-苏式-3'，4'-亚乙基二氧基-1-苯基-2-棕榈酰氨基-3-吡咯烷基-1-丙醇和D-苏式-4'-羟基-1-苯基-2-棕榈酰氨基-3-吡咯烷基-1-丙醇。这些抑制剂显著降低了MDCK细胞中的糖鞘脂水平，且没有细胞内神经酰胺的任何积累以及相关的生长抑制。随后，评估了每种抑制剂降低来自一名α-半乳糖苷酶A缺乏症患者的病毒转化淋巴细胞中糖脂水平的能力。两种化合物均显著降低了淋巴细胞中的中性糖鞘脂水平，且没有任何形态变化和生长抑制。此外，将这些抑制剂应用于法布里病的小鼠基因敲除模型。抑制剂治疗阻止了小鼠肾脏、肝脏和心脏中球三糖神经酰胺（Gb3）的积累。与另一种葡萄糖神经酰胺合酶抑制剂N-丁基脱氧野尻霉素不同，这种治疗与体重或器官重量的任何显著变化无关，也没有免疫耗竭现象。这些结果表明，这些最新的PDMP同系物有望作为治疗糖鞘脂贮积症的治疗药物。
