N-(2-((S)-2-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)pyrazine-2-carboxamide

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: N-(2-((S)-2-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)pyrazine-2-carboxamide
• 英文别名: DB-310；N-[2-[(2S)-2-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]pyrazine-2-carboxamide
• 化学式: C₃₀H₃₈N₆O₆
• 分子量: 578.668
• InChiKey: UUQDSBNKBWJJPD-PFNDQIBQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  42
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  163
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-苯基-L-丙氨酸苄酯 在 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 72.0h， 生成 N-(2-((S)-2-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamoyl)pyrrolidin-1-yl)-2-oxoethyl)pyrazine-2-carboxamide
  参考文献：
  名称：

  LMP2 Inhibitors as a Potential Treatment for Alzheimer’s Disease

  摘要：

  The immunoproteasome (iP), an inducible proteasome variant harboring three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic endopeptidase complex subunit-1, and low molecular mass polypeptide-7 (LMP7), is involved in multiple facets of inflammatory responses. We recently reported that YU102, a dual inhibitor of the iP subunit LMP2 and the constitutive proteasome catalytic subunit beta 1, ameliorates cognitive impairments in mouse models of Alzheimer's disease (AD) independently of amyloid deposits. To investigate whether inhibition of LMP2 is sufficient to improve the cognitive functions of AD mice, here we prepared 37 YU102 analogues and identified a potent LMP2 inhibitor DB-310 (28) (IC50: 80.6 nM) with improved selectivity and permeability in cells overexpressing ABCB1 transporters. We show that DB-310 induces suppression of IL-1 alpha production in microglia cells and improves cognitive functions in the Tg2576 transgenic mouse model of AD. This study supports that inhibition of LMP2 is a promising therapeutic strategy for treatment of AD.

  DOI：

  10.1021/acs.jmedchem.0c00416

文献信息

• PROTEASOME INHIBITORS
  申请人：University of Kentucky Research Foundation

  公开号：US20190161516A1

  公开（公告）日：2019-05-30

  Unique epoxyketone compounds useful for inhibiting a proteasome in a cell, pharmaceutical compositions and methods of their use are provided herein.
• LMP2 Inhibitors as a Potential Treatment for Alzheimer’s Disease
  作者：Deepak Bhattarai、Min Jae Lee、Ahruem Baek、In Jun Yeo、Zachary Miller、Yu Mi Baek、Sukyeong Lee、Dong-Eun Kim、Jin Tae Hong、Kyung Bo Kim

  DOI：10.1021/acs.jmedchem.0c00416

  日期：2020.4.9

  The immunoproteasome (iP), an inducible proteasome variant harboring three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic endopeptidase complex subunit-1, and low molecular mass polypeptide-7 (LMP7), is involved in multiple facets of inflammatory responses. We recently reported that YU102, a dual inhibitor of the iP subunit LMP2 and the constitutive proteasome catalytic subunit beta 1, ameliorates cognitive impairments in mouse models of Alzheimer's disease (AD) independently of amyloid deposits. To investigate whether inhibition of LMP2 is sufficient to improve the cognitive functions of AD mice, here we prepared 37 YU102 analogues and identified a potent LMP2 inhibitor DB-310 (28) (IC50: 80.6 nM) with improved selectivity and permeability in cells overexpressing ABCB1 transporters. We show that DB-310 induces suppression of IL-1 alpha production in microglia cells and improves cognitive functions in the Tg2576 transgenic mouse model of AD. This study supports that inhibition of LMP2 is a promising therapeutic strategy for treatment of AD.