Rapid Assembly of a Library of Lipophilic Iminosugars via the Thiol-Ene Reaction Yields Promising Pharmacological Chaperones for the Treatment of Gaucher Disease
Rapid Assembly of a Library of Lipophilic Iminosugars via the Thiol-Ene Reaction Yields Promising Pharmacological Chaperones for the Treatment of Gaucher Disease
复制标题
DOI：
10.1021/jm201633y
复制
发表时间：
2012-03-22
影响因子：
7.3
通讯作者：
Withers, Stephen G.
中科院分区：
文献类型：
--
作者：
Goddard-Borger, Ethan D.;Tropak, Michael B.;Withers, Stephen G.
开发了一种利用硫醇-烯反应的高度不同的亲脂性亚氨基糖路线，能够快速合成带有各种不同亲脂性取代基的 16 种双脱氧亚氨基糖醇。酶动力学分析表明，其中许多产品是人葡萄糖脑苷脂酶的有效低纳摩尔抑制剂，可稳定酶至热变性高达 20 K。对戈谢病患者来源的成纤维细胞进行的基于细胞的测定表明，施用这些化合物可以将溶酶体葡萄糖脑苷脂酶活性水平提高治疗相关量，在 p.N370S 纯合子细胞中高达 3.2 倍p.L444P 突变纯合细胞中的 1.4 倍突变。几种化合物在相对较宽的剂量范围内引起酶活性的增加。这里汇总的数据说明了许多葡萄糖脑苷脂酶抑制剂常见的亲脂性部分如何用于优化先导化合物陪伴纤维素中蛋白质的能力。这种合成策略的灵活性使其成为快速优化糖苷酶抑制剂效力和药代动力学行为的有吸引力的方法。
A highly divergent route to lipophilic iminosugars that utilizes the thiol-ene reaction was developed to enable the rapid synthesis of a collection of 16 dideoxyiminoxylitols bearing various different lipophilic substituents. Enzyme kinetic analyses revealed that a number of these products are potent, low-nanomolar inhibitors of human glucocerebrosidase that stabilize the enzyme to thermal denaturation by up to 20 K. Cell based assays conducted on Gaucher disease patient derived fibroblasts demonstrated that administration of the compounds can increase lysosomal glucocerebrosidase activity levels by therapeutically relevant amounts, as much as 3.2-fold in cells homozygous for the p.N370S mutation and 1.4-fold in cells homozygous for the p.L444P mutation. Several compounds elicited this increase in enzyme activity over a relatively wide dosage range. The data assembled here illustrate how the lipophilic moiety common to many glucocerebrosidase inhibitors might be used to optimize a lead compound's ability to chaperone the protein in cellulo. The flexibility of this synthetic strategy makes it an attractive approach to the rapid optimization of glycosidase inhibitor potency and pharmacokinetic behavior.