N-{N-[(3-cyanobenzene)sulfonyl]-4(R)-cyclobutylamino-(L)-prolyl}-4-[(3',5'-dichloroisonicotinoyl)amino]-(L)-phenylalanine ethyl ester | 865110-84-5

• 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: N-{N-[(3-cyanobenzene)sulfonyl]-4(R)-cyclobutylamino-(L)-prolyl}-4-[(3',5'-dichloroisonicotinoyl)amino]-(L)-phenylalanine ethyl ester
• 英文别名: (S)-ethyl 2-((2S,4R)-1-(3-cyanophenylsulfonyl)-4-(cyclobutylamino)pyrrolidine-2-carboxamido)-3-(4-(3,5-dichloroisonicotinamido)phenyl)propanoate；ethyl (2S)-2-[[(2S,4R)-1-(3-cyanophenyl)sulfonyl-4-(cyclobutylamino)pyrrolidine-2-carbonyl]amino]-3-[4-[(3,5-dichloropyridine-4-carbonyl)amino]phenyl]propanoate
• CAS: 865110-84-5
• 化学式: C₃₃H₃₄Cl₂N₆O₆S
• 分子量: 713.642
• InChiKey: YNSVZSPFLAGJJY-MHZHKKNFSA-N

物化性质

• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  48
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  179
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N-{N-[(3-cyanobenzene)sulfonyl]-4(R)-cyclobutylamino-(L)-prolyl}-4-[(3',5'-dichloroisonicotinoyl)amino]-(L)-phenylalanine ethyl ester 在 lithium hydroxide 作用下， 以 水 、 乙腈 为溶剂， 反应 2.0h， 生成 N-{N-[(3-cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(L)-prolyl}-4-[(3',5'-dichloroisonicotinoyl)amino]-(L)-phenylalanine
  参考文献：
  名称：

  [EN] VLA-4 ANTAGONISTS
  [FR] ANTAGONISTES DE VLA-4

  摘要：

  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过程中非常有用。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。

  公开号：

  WO2005087760A1
• 作为产物：
  描述：

  N-[4(R)-cyclobutylamino-(L)-prolyl]-4-[(3',5'-dichloroisonicotinoyl)amino]-(L)-phenylalanine ethyl ester hydrochloride 、 3-氰基苯磺酰氯 在 4-二甲氨基吡啶 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 3.0h， 以93%的产率得到N-{N-[(3-cyanobenzene)sulfonyl]-4(R)-cyclobutylamino-(L)-prolyl}-4-[(3',5'-dichloroisonicotinoyl)amino]-(L)-phenylalanine ethyl ester
  参考文献：
  名称：

  Discovery of N-{N-[(3-Cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(l)-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-(l)-phenylalanine (MK-0668), an Extremely Potent and Orally Active Antagonist of Very Late Antigen-4

  摘要：

  Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.

  DOI：

  10.1021/jm900257b

文献信息

• [EN] VLA-4 ANTAGONISTS<br/>[FR] ANTAGONISTES DE VLA-4
  申请人：MERCK & CO INC

  公开号：WO2005087760A1

  公开（公告）日：2005-09-22

  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过程中非常有用。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。
• Discovery of <i>N</i>-{<i>N</i>-[(3-Cyanophenyl)sulfonyl]-4(<i>R</i>)-cyclobutylamino-(<scp>l</scp>)-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-(<scp>l</scp>)-phenylalanine (MK-0668), an Extremely Potent and Orally Active Antagonist of Very Late Antigen-4
  作者：Linus S. Lin、Thomas Lanza、James P. Jewell、Ping Liu、Carrie Jones、Gerard R. Kieczykowski、Kelly Treonze、Qian Si、Salony Manior、Gloria Koo、Xinchun Tong、Junying Wang、Anne Schuelke、James Pivnichny、Regina Wang、Conrad Raab、Stella Vincent、Philip Davies、Malcolm MacCoss、Richard A. Mumford、William K. Hagmann

  DOI：10.1021/jm900257b

  日期：2009.6.11

  Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.