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本文引用的文献

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Design of Potent Inhibitors for Human Brain Memapsin 2 (-Secretase).人脑海马型天冬氨酸蛋白酶2（β-分泌酶）强效抑制剂的设计
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BACE1 inhibitor drugs in clinical trials for Alzheimer's disease.用于阿尔茨海默病临床试验的β-分泌酶1（BACE1）抑制剂药物。
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Structure-based design, synthesis and biological evaluation of novel β-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand.基于结构的新型β-分泌酶抑制剂的设计、合成及生物学评价，该抑制剂含有吡唑或噻唑部分作为P3配体。
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BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease.用于治疗阿尔茨海默病的β-分泌酶1（BACE1）抑制剂。
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Current concepts in Alzheimer's Disease: molecules, models and translational perspectives.阿尔茨海默病的当前概念：分子、模型和转化视角。
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Structure-based design of highly selective β-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.基于结构的高选择性β-分泌酶抑制剂设计：合成、生物学评价和蛋白-配体 X 射线晶体结构。
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以双环异恶唑啉甲酰胺作为P3配体的新型β-分泌酶1（BACE1）抑制剂的设计、合成、X射线研究及生物学评价

Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand.

作者信息

Ghosh Arun K, Ghosh Koena, Brindisi Margherita, Lendy Emma K, Yen Yu-Chen, Kumaragurubaran Nagaswamy, Huang Xiangping, Tang Jordan, Mesecar Andrew D

机构信息

Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States.

Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States.

出版信息

Bioorg Med Chem Lett. 2018 Aug 15;28(15):2605-2610. doi: 10.1016/j.bmcl.2018.06.045. Epub 2018 Jun 26.

DOI:10.1016/j.bmcl.2018.06.045
PMID:29970308
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6085084/
Abstract

We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 K value of 10.9 nM and EC of 343 nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85 Å resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature.

摘要

我们描述了新型β-分泌酶1（BACE1）抑制剂的设计、合成、X射线研究及生物学评估，这些抑制剂含有双环异恶唑啉甲酰胺作为P3配体，并与甲基半胱氨酸、甲基磺酰丙氨酸和Boc-氨基丙氨酸作为P2配体相结合。抑制剂3a的BACE1抑制常数（K值）为10.9 nM，半数效应浓度（EC）为343 nM。以2.85 Å的分辨率测定了与BACE1活性位点结合的3a的X射线结构。该结构表明，BACE1与双环四氢呋喃基异恶唑啉杂环之间的主要分子相互作用本质上是范德华力。