Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain[S]
Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain[S]
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基于特性的葡萄糖神经酰胺合酶抑制剂设计，可减少大脑中的葡萄糖神经酰胺[S]
DOI：
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发表时间：
2012
影响因子：
6.5
通讯作者：
J. Shayman
中科院分区：
文献类型：
--
作者：
Scott D. Larsen;Michael W. Wilson;A. Abe;L. Shu;Christopher H. George;P. Kirchhoff;H. D. Hollis Showalter;J. Xiang;R. Keep;J. Shayman
合成抑制是糖基神经酰胺合成酶（GCS）抑制剂酒石酸依利司他治疗1型戈谢病的基础。然而，依利司他及相关化合物用于治疗具有中枢神经系统表现的鞘糖脂储存疾病的扩展使用受到该药物缺乏脑渗透的限制。围绕d -三-1-苯基-2-癸烷氨基-3- morpholinos -propanol （PDMP）药效团进行性质建模，以寻找对GCS具有相当活性但缺乏p -糖蛋白（MDR1）识别的化合物。对羧基酰胺n -酰基进行了修饰，以降低总极性表面积和可旋转键数。在粗酶和全细胞实验中筛选化合物抑制GCS，并对MDR1底物进行识别。一种类似物2-（2,3-二氢- 1h -吲哚-2-基）- n- (（1R,2R)-1-（2,3-二氢苯并[b][1,4]二恶英-6-基）-1-羟基-3-（吡咯烷-1-基）丙烷-2-基）乙酰胺（CCG-203586）在低纳摩尔浓度下抑制GCS， MDR1几乎没有明显的识别。给小鼠腹腔注射这种化合物3天会导致脑葡萄糖神经酰胺含量显著的剂量依赖性降低，这种效果在与酒石酸eligustat同时给药的小鼠中没有观察到。
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-decanoylamino-3-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-hydroxy-3-(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.
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影响因子：
15.9
作者：
Liu, YJ;Wada, R;Proia, RL
通讯作者：
Proia, RL
影响因子：
2.7
作者：
ABE, A;INOKUCHI, J;RADIN, NS
通讯作者：
RADIN, NS
影响因子：
15.9
作者：
Abe, A;Gregory, S;Shayman, JA
通讯作者：
Shayman, JA
大鼠脉络丛原代细胞培养物和来自 PEPT2 缺失小鼠的脉络丛全组织中的肌肽摄取。
DOI：
10.1111/j.1471-4159.2004.02333.x
发表时间：
2004
期刊：
Journal of neurochemistry.
影响因子：
--
作者：
Teuscher,NathanS;Shen,Hong;Shu,Cathaleen;Xiang,Jianming;Keep,RichardF;Smith,DavidE
通讯作者：
Smith,DavidE