tert-butyl [(2S,3S)-3-hydroxy-1-(isobutylamino)-1-oxohexan-2-yl]carbamate | 1399317-73-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: tert-butyl [(2S,3S)-3-hydroxy-1-(isobutylamino)-1-oxohexan-2-yl]carbamate
• 英文别名: tert-Butyl [(2S,3S)-3-Hydroxy-1-(isobutylamino)-1-oxohexan-2-yl]carbamate；tert-butyl N-[(2S,3S)-3-hydroxy-1-(2-methylpropylamino)-1-oxohexan-2-yl]carbamate
• CAS: 1399317-73-7
• 化学式: C₁₅H₃₀N₂O₄
• 分子量: 302.414
• InChiKey: DTQQERNNRZYAOD-RYUDHWBXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  21
• 可旋转键数：
  9
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.87
• 拓扑面积：
  87.7
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl [(2S,3S)-3-hydroxy-1-(isobutylamino)-1-oxohexan-2-yl]carbamate 在 三乙酰氧基硼氢化钠 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 33.0h， 生成 3-ethyl-N-[(2S)-1-[[(2S,3S)-3-hydroxy-1-(2-methylpropylamino)-1-oxohexan-2-yl]amino]-3-phenylpropan-2-yl]-9-methyl-10,10-dioxo-10lambda6-thia-1,9-diazatricyclo[6.4.1.04,13]trideca-2,4(13),5,7-tetraene-6-carboxamide
  参考文献：
  名称：

  Structure-Based Design of Highly Selective β-Secretase Inhibitors: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure

  摘要：

  The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective beta-secretase inhibitors are described. The inhibitors are designed specifically to interact with S-1' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K-i = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.

  DOI：

  10.1021/jm3008823
• 作为产物：
  描述：

  (2R,3S)-ethyl 2,3-dihydroxyhexanoate 在 sodium azide 、 lithium hydroxide monohydrate 、 10% Pd/C 、 氢气 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 80.0h， 生成 tert-butyl [(2S,3S)-3-hydroxy-1-(isobutylamino)-1-oxohexan-2-yl]carbamate
  参考文献：
  名称：

  Structure-Based Design of Highly Selective β-Secretase Inhibitors: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure

  摘要：

  The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective beta-secretase inhibitors are described. The inhibitors are designed specifically to interact with S-1' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K-i = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.

  DOI：

  10.1021/jm3008823

文献信息

• Highly Selective and Potent Human β‐Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X‐ray Structure and Structure–Activity Relationship Studies
  作者：Arun K. Ghosh、Margherita Brindisi、Yu‐Chen Yen、Emma K. Lendy、Satish Kovela、Emilio Leal Cárdenas、Bhavanam Sekhara Reddy、Kalapala Venketeswara Rao、Deborah Downs、Xiangping Huang、Jordan Tang、Andrew D. Mesecar

  DOI：10.1002/cmdc.201800725

  日期：——

  was determined. Based on this structure, a computational docking study was performed which led to inhibitor 2 a-bound BACE2 models. These were used to optimize the potency and selectivity of inhibitors. A systematic structure-activity relationship study led to the identification of determinants of the inhibitors' potency and selectivity toward the BACE2 enzyme. Inhibitors 2 d [N3 -[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S

  本文中，我们介绍了有效的和高度选择性的β-分泌酶2（memapsin 1，β位淀粉样蛋白前体蛋白裂解酶2或BACE 2）抑制剂的设计，合成和生物学评估。BACE2被公认为是2型糖尿病激动人心的新靶标。BACE1的X射线结构与抑制剂2 a N3-[（1S，2R）-1-苄基-2-羟基-3-[[（1S，2S）-2-羟基-1-（异丁基氨基甲酰基）丙基测定了含有羟乙胺等排异构体的[氨基]丙基] -5- [甲基（甲基磺酰基）氨基] -N1-[（（1R）-1-苯基丙基]苯-1,3-二甲酰胺）。基于该结构，进行了计算对接研究，其导致了抑制剂2a-结合的BACE2模型。这些用于优化抑制剂的效力和选择性。一项系统的结构-活性关系研究导致确定抑制剂对BACE2酶的效力和选择性的决定因素。抑制剂2 d [N3-[（1S，2R）-1-苄基-2-羟基-3-[[（1S，2S）-2-羟基-1-（异丁基氨基甲酰基）戊基]氨基]丙基]
• Design of potent and highly selective inhibitors for human β-secretase 2 (memapsin 1), a target for type 2 diabetes
  作者：Arun K. Ghosh、Bhavanam Sekhara Reddy、Yu-Chen Yen、Emilio L. Cárdenas、Kalapala Venkateswara Rao、Deborah Downs、Xiangping Huang、Jordan Tang、Andrew D. Mesecar

  DOI：10.1039/c5sc03718b

  日期：——

  Structure-based design and syntheses of potent and highly selective BACE2 inhibitors are described.

  描述了有效和高度选择性的BACE2抑制剂的基于结构的设计和合成。
• Inhibitors of Memapsin 2 Cleavage for the Treatment of Alzheimer's Disease
  申请人：Purdue Research Foundation

  公开号：US20140066488A1

  公开（公告）日：2014-03-06

  Proteases such as memapsin 2 are important enzymes, playing roles in a variety of diseases including Alzheimer's Disease. The inventors have developed inhibitors of memapsin 2 and methods of use therefore in the treatment of disease.

  蛋白酶如memapsin 2是重要的酶，发挥着在多种疾病中的作用，包括阿尔茨海默病。发明人已经开发了memapsin 2的抑制剂以及使用这些抑制剂治疗疾病的方法。
• Structure-Based Design of Highly Selective β-Secretase Inhibitors: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure
  作者：Arun K. Ghosh、Kalapala Venkateswara Rao、Navnath D. Yadav、David D. Anderson、Navnath Gavande、Xiangping Huang、Simon Terzyan、Jordan Tang

  DOI：10.1021/jm3008823

  日期：2012.11.8

  The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective beta-secretase inhibitors are described. The inhibitors are designed specifically to interact with S-1' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K-i = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.