ethyl (2S)-2-[[(2S,4R)-4-(azetidin-1-yl)-1-(3-cyanophenyl)sulfonylpyrrolidine-2-carbonyl]amino]-3-[4-[(3,5-dichloropyridine-4-carbonyl)amino]phenyl]propanoate | 865110-11-8

• 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: ethyl (2S)-2-[[(2S,4R)-4-(azetidin-1-yl)-1-(3-cyanophenyl)sulfonylpyrrolidine-2-carbonyl]amino]-3-[4-[(3,5-dichloropyridine-4-carbonyl)amino]phenyl]propanoate
• CAS: 865110-11-8
• 化学式: C₃₂H₃₂Cl₂N₆O₆S
• 分子量: 699.615
• InChiKey: IPJCFIQBTVZQGU-UIUQJESISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  47
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  170
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  ethyl (2S)-2-[[(2S,4R)-4-(azetidin-1-yl)-1-(3-cyanophenyl)sulfonylpyrrolidine-2-carbonyl]amino]-3-[4-[(3,5-dichloropyridine-4-carbonyl)amino]phenyl]propanoate 在 水 、 lithium hydroxide 作用下， 以 乙腈 为溶剂， 生成 (S)-2-((2S,4R)-4-(azetidin-1-yl)-1-(3-cyanophenylsulfonyl)pyrrolidine-2-carboxamido)-3-(4-(3,5-dichloroisonicotinamido)phenyl)propanoic acid
  参考文献：
  名称：

  Discovery of N-{N-[(3-cyanobenzene) sulfonyl]-4(R)-(3,3-difluoropiperidin-1-yl)-(l)-prolyl}-4-[(3′,5′-dichloro-isonicotinoyl) amino]-(l)-phenylalanine (MK-0617), a highly potent and orally active VLA-4 antagonist

  摘要：

  A series of prolyl-N-isonicotinoyl-(L)-4-aminophenylalanine derivatives substituted at the proline 4-position with cyclic amines was evaluated as VLA-4 antagonists. The ring size and presence or absence of fluorine affected potency and receptor occupancy. The analog with 3,3-difluoropiperidine at the proline 4-position (13) was the most potent compound and had very good duration of receptor occupancy in vitro. The ethyl ester prodrug of 13 demonstrated excellent receptor occupancy after oral dosing in rats. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.07.111
• 作为产物：
  描述：

  、 N-isonicotinoyl-(L)-4-aminophenylalanine 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 ethyl (2S)-2-[[(2S,4R)-4-(azetidin-1-yl)-1-(3-cyanophenyl)sulfonylpyrrolidine-2-carbonyl]amino]-3-[4-[(3,5-dichloropyridine-4-carbonyl)amino]phenyl]propanoate
  参考文献：
  名称：

  Discovery of N-{N-[(3-cyanobenzene) sulfonyl]-4(R)-(3,3-difluoropiperidin-1-yl)-(l)-prolyl}-4-[(3′,5′-dichloro-isonicotinoyl) amino]-(l)-phenylalanine (MK-0617), a highly potent and orally active VLA-4 antagonist

  摘要：

  A series of prolyl-N-isonicotinoyl-(L)-4-aminophenylalanine derivatives substituted at the proline 4-position with cyclic amines was evaluated as VLA-4 antagonists. The ring size and presence or absence of fluorine affected potency and receptor occupancy. The analog with 3,3-difluoropiperidine at the proline 4-position (13) was the most potent compound and had very good duration of receptor occupancy in vitro. The ethyl ester prodrug of 13 demonstrated excellent receptor occupancy after oral dosing in rats. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.07.111

文献信息

• Vla-4 antagonists
  申请人：Hagmann K. William

  公开号：US20070179190A1

  公开（公告）日：2007-08-02

  Compounds of Formula I are antagonists of VLA-4, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of inflammatory bowel disease including ulcerative colitis and Crohn's disease, multiple sclerosis, asthma, and rheumatoid arthritis.

  公式I的化合物是VLA-4的拮抗剂，因此在抑制或预防细胞粘附和细胞粘附介导的病理方面非常有用。这些化合物可以制成药物组合物，并适用于治疗炎症性肠病，包括溃疡性结肠炎和克罗恩病、多发性硬化症、哮喘和类风湿性关节炎。
• US7514409B2
  申请人：——

  公开号：US7514409B2

  公开（公告）日：2009-04-07
• Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists
  作者：Thomas S. Reger、Jasmine Zunic、Nicholas Stock、Bowei Wang、Nicholas D. Smith、Benito Munoz、Mitchell D. Green、Michael F. Gardner、Joyce P. James、Weichao Chen、Kenneth Alves、Qian Si、Kelly M. Treonze、Russell B. Lingham、Richard A. Mumford

  DOI：10.1016/j.bmcl.2009.12.009

  日期：2010.2

  A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics. (C) 2009 Elsevier Ltd. All rights reserved.
• Discovery of N-{N-[(3-cyanobenzene) sulfonyl]-4(R)-(3,3-difluoropiperidin-1-yl)-(l)-prolyl}-4-[(3′,5′-dichloro-isonicotinoyl) amino]-(l)-phenylalanine (MK-0617), a highly potent and orally active VLA-4 antagonist
  作者：Shankar Venkatraman、Alec D. Lebsack、Kenneth Alves、Michael F. Gardner、Joyce James、Russell B. Lingham、Salony Maniar、Richard A. Mumford、Qian Si、Nicholas Stock、Kelly M. Treonze、Bowei Wang、Jasmine Zunic、Benito Munoz

  DOI：10.1016/j.bmcl.2009.07.111

  日期：2009.10

  A series of prolyl-N-isonicotinoyl-(L)-4-aminophenylalanine derivatives substituted at the proline 4-position with cyclic amines was evaluated as VLA-4 antagonists. The ring size and presence or absence of fluorine affected potency and receptor occupancy. The analog with 3,3-difluoropiperidine at the proline 4-position (13) was the most potent compound and had very good duration of receptor occupancy in vitro. The ethyl ester prodrug of 13 demonstrated excellent receptor occupancy after oral dosing in rats. (C) 2009 Elsevier Ltd. All rights reserved.