Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain
Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain
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DOI：
10.1194/jlr.m021261
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发表时间：
2012-02-01
影响因子：
6.5
通讯作者：
Shayman, James A.
中科院分区：
文献类型：
--
作者：
Larsen, Scott D.;Wilson, Michael W.;Shayman, James A.
合成抑制是葡萄糖神经酰胺合酶（GCS）抑制剂酒石酸依格列他治疗1型戈谢病的基础。然而，eliglustat和相关化合物用于治疗具有CNS表现的鞘糖脂贮积病的扩展使用受到该药物缺乏脑渗透的限制。围绕D-苏型-1-苯基-2-癸酰氨基-3-吗啉代-丙醇（PdR）药效团的性质建模用于寻找对GCS具有可比活性但缺乏P-糖蛋白（MDR 1）识别的化合物。对羧酰胺N-酰基进行修饰以降低总极性表面积和可旋转键数。在粗酶和全细胞测定中筛选化合物对GCS的抑制以及MDR 1底物识别。一种类似物2-（2，3-二氢-1H-茚-2-基）-N-（（1 R，2 R）-1-（2，3-二氢苯并[B][1，4]二恶英-6-基）-1-羟基-3-（吡咯烷-1-基）丙-2-基）乙酰胺（CCG-203586）在低纳摩尔浓度下抑制GCS，几乎不被MDR 1明显识别。向小鼠腹膜内给予该化合物3天导致脑葡糖神经酰胺含量显著剂量依赖性降低，在与酒石酸依格列他平行给药的小鼠中未观察到该效应。拉森，南达科他州，M.W.威尔逊，A.亚伯湖Shu，C.H.作者声明：乔治，P.肖沃尔特，J. Xiang，R. F.保持，和J.A.谢曼基于性质设计的葡糖神经酰胺合酶抑制剂，减少大脑中的葡糖神经酰胺。J. Lipid Res. 2012. 53：282-291。
Synthesis inhibition is the basis for the treatment of type 1 Gaucher disease by the glucosylceramide synthase (GCS) inhibitor eliglustat tartrate. However, the extended use of eliglustat and related compounds for the treatment of glycosphingolipid storage diseases with CNS manifestations is limited by the lack of brain penetration of this drug. Property modeling around the D-threo-1-phenyl-2-decanoylamino3- morpholino-propanol (PDMP) pharmacophore was employed in a search for compounds of comparable activity against the GCS but lacking P-glycoprotein (MDR1) recognition. Modifications of the carboxamide N-acyl group were made to lower total polar surface area and rotatable bond number. Compounds were screened for inhibition of GCS in crude enzyme and whole cell assays and for MDR1 substrate recognition. One analog, 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy3-(pyrrolidin-1-yl)propan-2-yl)acetamide (CCG-203586), was identified that inhibited GCS at low nanomolar concentrations with little to no apparent recognition by MDR1. Intraperitoneal administration of this compound to mice for 3 days resulted in a significant dose dependent decrease in brain glucosylceramide content, an effect not seen in mice dosed in parallel with eliglustat tartrate.-Larsen, S.D., M.W. Wilson, A. Abe, L. Shu, C.H. George, P. Kirchhoff, H.D.H. Showalter, J. Xiang, R.F. Keep, and J.A. Shayman. Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain. J. Lipid Res. 2012. 53: 282-291.