(2R,3R)-2-(cyclohexylmethyl)-6,6,6-trifluoro-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]hexanoic acid | 382135-53-7

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (2R,3R)-2-(cyclohexylmethyl)-6,6,6-trifluoro-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]hexanoic acid
• 英文别名: (2R,3S)-2-(cyclohexylmethyl)-6,6,6-trifluoro-3-[formyl(oxan-2-yloxy)amino]hexanoic acid
• CAS: 382135-53-7
• 化学式: C₁₉H₃₀F₃NO₅
• 分子量: 409.446
• InChiKey: BDDZNXDFQSMFPL-GARXDOFDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2R,3R)-2-(cyclohexylmethyl)-6,6,6-trifluoro-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]hexanoic acid 在 N-甲基吗啉 、 氰基磷酸二乙酯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (2R,3S)-2-(cyclohexylmethyl)-6,6,6-trifluoro-3-[formyl(hydroxy)amino]-N-[(2S)-5-[[(E)-N'-nitrocarbamimidoyl]amino]-1-oxo-1-(1,3-thiazol-2-ylamino)pentan-2-yl]hexanamide
  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
• 作为产物：
  描述：

  methyl (3R)-6,6,6-trifluoro-3-hydroxy-2-cyclohexylmethylhexanoate 在 吡啶 、 lithium hydroxide 、 sodium hydroxide 、 potassium carbonate 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙酸乙酯 、 丙酮 为溶剂， 反应 62.0h， 生成 (2R,3R)-2-(cyclohexylmethyl)-6,6,6-trifluoro-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]hexanoic acid
  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