强效β-分泌酶1（BACE1）抑制剂的设计、合成及构效关系分析：阿尔茨海默病潜在的先导药物候选物
Design, synthesis and SAR analysis of potent BACE1 inhibitors: Possible lead drug candidates for Alzheimer's disease.
作者信息
Tarazi Hamadeh, Odeh Raed Abu, Al-Qawasmeh Raed, Yousef Imad Abu, Voelter Wolfgang, Al-Tel Taleb H
机构信息
College of Pharmacy, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates.
Sharjah Institute for Medical Research, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates; College of Health Sciences, Department of Medical Laboratory Sciences, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates.
出版信息
Eur J Med Chem. 2017 Jan 5;125:1213-1224. doi: 10.1016/j.ejmech.2016.11.021. Epub 2016 Nov 12.
We have identified potent isophthalic acid derivatives armed with imidazol and indolyl groups as potent β-secretase inhibitors. The most effective analogs demonstrated low nano-molar potency for the BACE1 (β-secretase cleaving enzyme) as measured by FRET (Fluorescence Resonance Energy Transfer) and cell-based (ELISA) assays. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on previously reported hydroxyethylene transition state inhibitor derived from isophthalic acid I. In the FRET assay, the most potent compound, 10a, displayed an IC value for BACE1 of 75 nM, and exhibited cellular activity with an EC50 value of 0.81 μM. On the other hand, compound 11b was found to be the most potent compound in the cell-based assay with an EC value of 0.29 μM.
我们已鉴定出带有咪唑和吲哚基团的间苯二甲酸衍生物是有效的β-分泌酶抑制剂。通过荧光共振能量转移（FRET）和基于细胞的（ELISA）分析测定，最有效的类似物对β-分泌酶切割酶1（BACE1）显示出低纳摩尔效力。我们的设计策略遵循传统的构效关系方法，并得到基于先前报道的源自间苯二甲酸I的羟乙烯过渡态抑制剂的分子建模研究的支持。在FRET分析中，最有效的化合物10a对BACE1的IC值为75 nM，并表现出细胞活性，EC50值为0.81 μM。另一方面，在基于细胞的分析中发现化合物11b是最有效的化合物，EC值为0.29 μM。
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