基于结构的设计、合成及二氢喹唑啉类β-分泌酶抑制剂的生物学评价。
Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors.
机构信息
Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States.
出版信息
Bioorg Med Chem Lett. 2012 Sep 1;22(17):5460-5. doi: 10.1016/j.bmcl.2012.07.043. Epub 2012 Jul 20.
Abstract
Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13 nM) and cellular (IC(50)=21 nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.
摘要
本文描述了一系列基于二氢喹唑啉结构设计、合成和生物评价的β-分泌酶抑制剂，其中包含噻唑和吡唑衍生的 P2 配体。我们已经鉴定出抑制剂 4f，它在酶抑制（K(i)=13 nM）和细胞（在神经母细胞瘤细胞中 IC(50)=21 nM）测定中均表现出很强的活性。基于 3a 结合β-分泌酶的 X 射线结构，建立了 4f 的模型。该模型提出了在活性部位可能的相互作用。
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