(5S,1'S)-5-<1'--3'-methylbutyl>dihydrofuran-2(3H)-one | 105018-81-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: (5S,1'S)-5-<1'--3'-methylbutyl>dihydrofuran-2(3H)-one
• 英文别名: (5S)-5-[(1'S)-1-(N-Boc-amino)-3-methylbutyl]dihydrofuran-2(3H)-one；5(S)-5-<1(S)-1-(N-Boc-amino)-3-methylbutyl>dihydrofuran-2(3H)-one；(5S,1'S)-5-[1'-[(tert-butoxycarbonyl)amino]-3'-methylbutyl]-dihydrofuran-2(3H)-one；(5S,1’S)-5-[1‘-[(tert-butyloxycarbonyl)amino]-3’-methylbutyl]dihydrofuran-2(3H)-one；(5S)-5-[(1S)-1-(N-t-Butoxycarbonylamino)-3-methylbutyl]-dihydrofuran-2(3H)-one；4S,5S-7-Methyl-5-(t-butoxycarbonylamino)gamma-octanolactone；tert-butyl N-[(1S)-3-methyl-1-[(2S)-5-oxooxolan-2-yl]butyl]carbamate
• CAS: 105018-81-3
• 化学式: C₁₄H₂₅NO₄
• 分子量: 271.357
• InChiKey: VBSGVYVHEPQKTH-QWRGUYRKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (5S,1'S)-5-<1'--3'-methylbutyl>dihydrofuran-2(3H)-one 在 咪唑 、 正丁基锂 、 水 、 二异丙胺 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 40.33h， 生成 (2R,4S,5S)-5-[(fluorenylmethyloxycarbonyl)amino]-4-[(tert-butyldimethylsilyl)oxy]-2,7-dimethyloctanoic acid
  参考文献：
  名称：

  BRAIN PERMEANT PEPTIDOMIMETIC BETA-SECRETASE 1 INHIBITORS FOR THE TREATMENT OR PROPHYLAXIS OF NEUROLOGICAL DISORDERS OR CONDITIONS

  摘要：

  这项申请提出了一种新型的肽类模拟替代羟基乙烯化合物，这些化合物是β淀粉样蛋白裂解酶的抑制剂，能够渗透到大脑并在目标器官大脑中达到治疗浓度。这些化合物被纳入药物组合物中，并应用于治疗或预防神经系统疾病或症状以及其他疾病或症状，包括唐氏综合征和糖尿病。

  公开号：

  US20170296618A1
• 作为产物：
  描述：

  (1'R,2'S)-2-<2'--1'-<(tert-butyldimethylsilyl)oxy>-4'-methylpentyl>-1,3-thiazole 在 sodium tetrahydroborate 、 4 A molecular sieve 、 四丁基氟化铵 、 copper(II) oxide 、 copper dichloride 、 nickel dichloride 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 、 乙腈 为溶剂， 反应 48.92h， 生成 (5S,1'S)-5-<1'--3'-methylbutyl>dihydrofuran-2(3H)-one
  参考文献：
  名称：

  Thiazole-Based Stereoselective Routes to Leucine and Phenylalanine Hydroxyethylene Dipeptide Isostere Inhibitors of Renin and HIV-1 Aspartic Protease

  摘要：

  A new synthesis of hydroxyethylene dipeptide isosteres for Leu-Leu and Phe-Phe in their gamma-lactone form 1a and 1b employing beta-amino-alpha-hydroxy aldehydes with singly and doubly protected nitrogen has been developed. These key intermediates, which are available through the thiazole-aldehyde synthesis from L-leucine and L-phenylalanine, were converted to alkanoates by Wittig olefination and reduction of the ethylenic double bond. Lactonization and stereoselective alkylation at C-2 of the resulting lactones completed the building up of the structural framework. Overall yields were in the range 16-19% for 1a and 22-23% for 1b.

  DOI：

  10.1021/jo00129a037

文献信息

• Synthesis of β‐Secretase Inhibitors Containing a Hydroxyethylene Dipeptide Isostere
  作者：Xiaoming Yang、Xiaomin Zou、Yiqiu Fu、Ke Mou、Gang Fu、Chao Ma、Ping Xu

  DOI：10.1080/00397910600977509

  日期：2007.1.1

  Abstract β‐Secretase inhibitors with a Leu*Ala hydroxyethylene dipeptide (HED) isostere have been an especially interesting topic in recent years. In this study, a template compound 17 was synthesized, featuring truncation at the P2′ position and changes at P2 and P3, which differs from other reported potent inhibitors. The purpose was to explore optimal reaction conditions and construct an inhibitor

  摘要 近年来，具有 Leu*Ala 羟基乙烯二肽 (HED) 等排体的 β-分泌酶抑制剂一直是一个特别有趣的话题。本研究合成了模板化合物17，其P2'位置截断，P2和P3发生变化，与其他报道的强效抑制剂不同。目的是探索最佳反应条件并构建抑制剂库以研究理想的蛋白质-底物相互作用。
• [EN] BICYCLIC COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF<br/>[FR] COMPOSES BICYCLIQUES INHIBANT L'ACTIVITE DE LA BETA-SECRETASE ET PROCEDES D'UTILISATION ASSOCIES
  申请人：ZAPAQ INC

  公开号：WO2006034277A1

  公开（公告）日：2006-03-30

  The present invention provides bicyclic beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer’s disease.

  本发明提供了双环β-分泌酶抑制剂及其用途，包括用于治疗阿尔茨海默病的方法。
• Structure-Based Design:  Potent Inhibitors of Human Brain Memapsin 2 (β-Secretase)
  作者：Arun K. Ghosh、Geoffrey Bilcer、Cynthia Harwood、Reiko Kawahama、Dongwoo Shin、Khaja Azhar Hussain、Lin Hong、Jeffrey A. Loy、Chan Nguyen、Gerald Koelsch、Jacques Ermolieff、Jordan Tang

  DOI：10.1021/jm0101803

  日期：2001.8.1

  Memapsin 2 (beta-secretase) is one of two proteases that cleave the beta-amyloid precursor protein (APP) to produce the 40-42 residue amyloid-beta peptide (Abeta) in the human brain, a key event in the progression of Alzheimer's disease. On the basis of the X-ray crystal structure of our lead inhibitor (2, OM99-2 with eight residues) bound to memapsin, we have reduced the molecular weight and designed

  Memapsin 2（beta-secretase）是两种蛋白酶，它们会切割β-淀粉样蛋白前体蛋白（APP）在人脑中产生40-42个残基的淀粉样β-肽（Abeta），这是阿尔茨海默氏病进展的关键事件疾病。基于我们的铅抑制剂（2个，带有八个残基的OM99-2，具有8个残基）的X射线晶体结构，我们降低了分子量，并设计了有效的Memapsin抑制剂。已经提出了基于结构的设计和初步的结构活性研究。
• Amino-Containing Compounds Which Inhibit Memapsin 2 Beta-Secretase Activity and Methods of Use Thereof
  申请人：Ghosh Arun K.

  公开号：US20080125467A1

  公开（公告）日：2008-05-29

  The present invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer's disease.

  本发明提供了新型β-分泌酶抑制剂及其使用方法，包括治疗阿尔茨海默病的方法。
• Inhibitors of memapsin 2 and use thereof
  申请人：Oklahoma Medical Research Foundation

  公开号：US20030092629A1

  公开（公告）日：2003-05-15

  Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed-, The substrate and subsite specificity of the catalytically active enzyme have been determined by a method which determines the initial hydrolysis rate of the substrates by using MALDI-TOF/MS. Alternatively, the subsite specificity of memapsin can be determined by probing a library of inhibitors with memapsin 2 and subsequently detecting the bound memapsin 2 with an antibody raised to memapsin 2 and an alkaline phosphatase conjugated secondary antibody. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the more than seventy substrate analogues were synthesized, among which MMI-005, MMI-012, MMI-017, MMI-018, MMI-025, MMI-026, MMI-037, MMI-039, MMI-040, MMI-066, MMI-070, and MMI-071 have inhibition constants in the range of 1.4-61.4×10 −9 M against recombinant pro-memapsin 2. These inhibitors are useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.

  已开发出生产纯化、具有催化活性的重组memapsin 2的方法。通过一种方法确定了具有催化活性的酶的底物和亚位点特异性，该方法利用MALDI-TOF/MS测定了底物的初始水解速率。另外，memapsin的亚位点特异性可以通过使用memapsin 2探测抑制剂库，并随后使用对memapsin 2产生的抗体和碱性磷酸酶结合的二抗检测已结合的memapsin 2来确定。底物和亚位点特异性信息被用来设计模拟天然memapsin 2底物的底物类似物，可以抑制memapsin 2的功能。这些底物类似物基于肽序列，已证明与memapsin 2的天然肽底物相关。底物类似物包含至少一个酰胺键的类似物，该键无法被memapsin 2水解。开发了包括在关键氨基酸残基位点处的同位素的底物类似物合成过程，合成了七十多种底物类似物，其中MMI-005、MMI-012、MMI-017、MMI-018、MMI-025、MMI-026、MMI-037、MMI-039、MMI-040、MMI-066、MMI-070和MMI-071对重组前memapsin 2的抑制常数在1.4-61.4×10^-9M范围内。这些抑制剂在诊断和治疗和/或预防阿尔茨海默病中非常有用。