((6S,7R,12S,15S)-methyl 6,9-dibenzyl-7-hydroxy-12-isobutyl-15-isopropyl-2,2-dimethyl-4,10,13-trioxo-3-oxa-5,9,11,14-tetraazahexadecan-16-oate) | 398515-96-3

• 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: ((6S,7R,12S,15S)-methyl 6,9-dibenzyl-7-hydroxy-12-isobutyl-15-isopropyl-2,2-dimethyl-4,10,13-trioxo-3-oxa-5,9,11,14-tetraazahexadecan-16-oate)
• 英文别名: Jia097；31C；Wpe-III-31C；methyl (2S)-2-[[(2S)-2-[[benzyl-[(2R,3S)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-phenylbutyl]carbamoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoate
• CAS: 398515-96-3
• 化学式: C₃₅H₅₂N₄O₇
• 分子量: 640.82
• InChiKey: DINAVFJXFRFCRE-ZXYZSCNASA-N

物化性质

• 沸点：
  832.6±65.0 °C(Predicted)
• 密度：
  1.135±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥9mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  46
• 可旋转键数：
  18
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  146
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ((6S,7R,12S,15S)-methyl 6,9-dibenzyl-7-hydroxy-12-isobutyl-15-isopropyl-2,2-dimethyl-4,10,13-trioxo-3-oxa-5,9,11,14-tetraazahexadecan-16-oate) 在 lithium hydroxide 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 (S)-2-((S)-2-{(S)-2-[3-Benzyl-3-((2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-4-methyl-pentanoylamino}-3-methyl-butyrylamino)-3-methyl-butyric acid methyl ester
  参考文献：
  名称：

  Probing pockets S2–S4′ of the γ-secretase active site with (hydroxyethyl)urea peptidomimetics

  摘要：

  (Hydroxyethyl)urea peptidomimetics are potent inhibitors of gamma-secretase that are accessible in a few synthetic steps. Systematic alteration of P2-P4' revealed that the corresponding S2-S4' active site pockets accommodate a variety of substituents, consistent with the fact that this protease cleaves a variety of single-pass membrane proteins; however, phenylalanine is not well tolerated at P2'. A compound spanning P2-P3' was identified as a low nM inhibitor of gamma-secretase activity both in cells and under cell-free conditions. (C) 2004 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2004.01.077
• 作为产物：
  描述：

  1-苄基-2,3-环氧正丙基-氨基甲酸叔丁酯 在 lithium hydroxide 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 异丙醇 为溶剂， 生成 ((6S,7R,12S,15S)-methyl 6,9-dibenzyl-7-hydroxy-12-isobutyl-15-isopropyl-2,2-dimethyl-4,10,13-trioxo-3-oxa-5,9,11,14-tetraazahexadecan-16-oate)
  参考文献：
  名称：

  Unnatural Amino Acid-Substituted (Hydroxyethyl)urea Peptidomimetics Inhibit γ-Secretase and Promote the Neuronal Differentiation of Neuroblastoma Cells

  摘要：

  γ-分泌酶作为一种天冬氨酸蛋白酶，介导β淀粉样蛋白前体蛋白(APP)和Notch的跨膜蛋白水解作用，被认为是阿尔茨海默病(AD)治疗药物开发的主要药理学靶点。为了鉴定阻断γ-分泌酶介导的蛋白水解作用的化合物，我们使用了一种高度灵敏的基于细胞的报告基因检测方法，其中表达Gal4/VP16标记的C99-APP作为γ-分泌酶的直接底物，经过γ-分泌酶切割释放的Gal4/VP16标记的APP胞内域激活Gal4驱动的荧光素酶报告基因的表达。利用这一报告检测方法，我们证明新合成的(羟乙基)脲类拟肽，在P1′和/或P3′位置含有非天然氨基酸基团，能有效抑制γ-分泌酶活性并显著减少Aβ产生。γ-分泌酶依赖的Notch S3切割也被这些(羟乙基)脲类持续阻断，通过减少Notch胞内域的生成来证实，这是Notch信号激活的前提。活性Jia化合物抑制Notch信号有效地促进神经母细胞瘤细胞的神经分化，干预神经母细胞瘤的形成和恶性。我们的结果表明，含有非天然氨基酸替代的(羟乙基)脲类拟肽可能代表一类新的具有增强稳定性的γ-分泌酶抑制剂，为进一步开发有效的AD和神经母细胞瘤治疗药物提供了基础。

  DOI：

  10.1124/mol.106.024299

文献信息

• Stereochemical Analysis of (Hydroxyethyl)urea Peptidomimetic Inhibitors of γ-Secretase
  作者：Pancham Bakshi、Michael S. Wolfe

  DOI：10.1021/jm049566e

  日期：2004.12.1

  (Hydroxyethyl)urea peptidomimetics systematically altered at positions P2-P3' with hydrophobic D-amino acids were synthesized. An all D-amino acid containing analogue was identified that effectively blocked gamma-secretase activity in a cell-free system (IC50 = 30 nM). Systematic alteration of the stereocenters of a potent compound revealed interdependence between the various positions. Although typically less potent than their L-peptidomimetic counterparts. selected all D-amino acid containing analogues were equipotent. to their counterparts in a cell-based assay when incubated for extended times.
• Blockade of gamma-secretase activity to promote myelination by oligodendrocytes
  申请人：Watkins Alan Trent

  公开号：US20070225228A1

  公开（公告）日：2007-09-27

  Methods are provided for enhancing myelination. Myelination is enhanced by administration of agents that are inhibitors of γ-secretase. Methods of screening for pharmaceutically active compounds that enhance myelination, and for genes involved in myelination are also provided.
• METHOD OF TREATING ALZHEIMER'S DISEASE USING PHARMACOLOGICAL CHAPERONES TO INCREASE PRESENILIN FUNCTION AND GAMMA-SECRETASE ACTIVITY
  申请人：Wustman Brandon

  公开号：US20130102538A1

  公开（公告）日：2013-04-25

  The present invention relates to a method for treating an individual having Alzheimer's Disease by using pharmacological chaperones that bind presenelin and thereby increase γ-secretase activity.
• US7973011B2
  申请人：——

  公开号：US7973011B2

  公开（公告）日：2011-07-05
• US8377886B2
  申请人：——

  公开号：US8377886B2

  公开（公告）日：2013-02-19