(2R,3S)-3-(Formyl-hydroxy-amino)-4-methyl-2-(4-methyl-cyclohexylmethyl)-pentanoic acid [(S)-4-({amino-[(E)-pyridine-2-sulfonylimino]-methyl}-amino)-1-(thiazol-2-ylcarbamoyl)-butyl]-amide | 383174-01-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (2R,3S)-3-(Formyl-hydroxy-amino)-4-methyl-2-(4-methyl-cyclohexylmethyl)-pentanoic acid [(S)-4-({amino-[(E)-pyridine-2-sulfonylimino]-methyl}-amino)-1-(thiazol-2-ylcarbamoyl)-butyl]-amide
• 英文别名: (I+/-R)-I+/--[(1S)-1-(Formylhydroxyamino)-2-methylpropyl]-N-[(1S)-4-[[imino[(2-pyridinylsulfonyl)amino]methyl]amino]-1-[(2-thiazolylamino)carbonyl]butyl]-4-methylcyclohexanepropanamide；(2R,3S)-N-[(2S)-5-[[amino-(pyridin-2-ylsulfonylamino)methylidene]amino]-1-oxo-1-(1,3-thiazol-2-ylamino)pentan-2-yl]-3-[formyl(hydroxy)amino]-4-methyl-2-[(4-methylcyclohexyl)methyl]pentanamide
• CAS: 383174-01-4
• 化学式: C₂₉H₄₄N₈O₆S₂
• 分子量: 664.85
• InChiKey: UBBKFTZMBAKVDC-OSBIAPMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  45
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  246
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  吡啶-2-磺酰氯 在 N-甲基吗啉 、 盐酸 、 sodium hydroxide 、 氰基磷酸二乙酯 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 46.0h， 生成 (2R,3S)-3-(Formyl-hydroxy-amino)-4-methyl-2-(4-methyl-cyclohexylmethyl)-pentanoic acid [(S)-4-({amino-[(E)-pyridine-2-sulfonylimino]-methyl}-amino)-1-(thiazol-2-ylcarbamoyl)-butyl]-amide
  参考文献：
  名称：

  Design of Selective and Soluble Inhibitors of Tumor Necrosis Factor-α Converting Enzyme (TACE)

  摘要：

  A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMPI and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.

  DOI：

  10.1021/jm0102654

文献信息

• Design of Selective and Soluble Inhibitors of Tumor Necrosis Factor-α Converting Enzyme (TACE)
  作者：Michael H. Rabinowitz、Robert C. Andrews、J. David Becherer、D. Mark Bickett、Dulce G. Bubacz、James G. Conway、David J. Cowan、Micheal Gaul、Kimberly Glennon、Millard H. Lambert、M. Anthony Leesnitzer、Darryl L. McDougald、Marcia L. Moss、David L. Musso、Michele C. Rizzolio

  DOI：10.1021/jm0102654

  日期：2001.11.1

  A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMPI and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.