(2R,3S)-6,6,6-trifluoro-3-[formyl(tetrahydro-2H-pyran-yloxy)amino]-2-isobutylhexanoic acid | 212610-69-0

• 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,3S)-6,6,6-trifluoro-3-[formyl(tetrahydro-2H-pyran-yloxy)amino]-2-isobutylhexanoic acid
• 英文别名: (2R,3S)-6,6,6-trifluoro-3-[formyl(oxan-2-yloxy)amino]-2-(2-methylpropyl)hexanoic acid
• CAS: 212610-69-0
• 化学式: C₁₆H₂₆F₃NO₅
• 分子量: 369.381
• InChiKey: LJSMMARXIOPLNE-AMIUJLCOSA-N

物化性质

• 沸点：
  435.7±55.0 °C(predicted)
• 密度：
  1.22±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.88
• 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,3S)-6,6,6-trifluoro-3-[formyl(tetrahydro-2H-pyran-yloxy)amino]-2-isobutylhexanoic 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)-6,6,6-Trifluoro-3-(formyl-hydroxy-amino)-2-isobutyl-hexanoic acid [(1S,2R)-4-({amino-[(E)-methanesulfonylimino]-methyl}-amino)-2-methyl-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
• 作为产物：
  描述：

  Methanesulfonic acid (1R,2R)-4-methyl-2-(tetrahydro-pyran-2-yloxycarbamoyl)-1-(3,3,3-trifluoro-propyl)-pentyl ester 在 吡啶 、 sodium hydroxide 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 丙酮 为溶剂， 反应 38.0h， 生成 (2R,3S)-6,6,6-trifluoro-3-[formyl(tetrahydro-2H-pyran-yloxy)amino]-2-isobutylhexanoic 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

文献信息

• [EN] REVERSE HYDROXAMATE DERIVATIVES AS METALLOPROTEASE INHIBITORS<br/>[FR] DERIVES D'HYDROXAMATE UTILISES COMME INHIBITEURS DE METALLOPROTEASE
  申请人：GLAXO GROUP LIMITED

  公开号：WO1998038179A1

  公开（公告）日：1998-09-03

  (EN) A family of compounds having general structural formula (I) wherein W is a reverse hydroxamic acid group (a); R5 is hydrogen or lower alkyl; R6 is (b); where Z1 is heteroarylene; preferably: R1 is methyl, ethyl, isopropyl, n-propyl or 3,3,3-trifluoro-n-propyl; R2 is isobutyl or sec-butyl; R3 is hydrogen; R4 is tert-butyl, sec-butyl, 1-methoxy-1-ethyl or 2-(2-pyridylcarbonylamino)-1-ethyl; R5 is hydrogen; and R6 is 2-thiazolyl or 2-pyridyl. Such compounds show potent inhibition of MMP's, cell-free TNF convertase enzyme and TNF release from cells, and in some cases inhibit TNF convertase and TNF release from cells in preference to matrix metalloproteases.(FR) L'invention concerne des composés présentant la formule structurelle générale (I) où W est un groupe acide hydroxamique inverse (a); R5 est de l'hydrogène ou un alkyle inférieur; R6 est (b), où Z1 est de l'hétéroarylène; de préférence, R1 représente méthyle, éthyle, isopropyle, n-propyle ou 3,3,3-trifluoro-n-propyle; R2 est de l'isobutyle ou sec-butyle; R3 est de l'hydrogène; R4 est du tert-butyle, sec-butyle, 1-méthoxy-1-éthyle ou 2-(2-pyridylcarbonylamino)-1-éthyle, R5 est de l'hydrogène; et R6 est du 2-thiazolyle ou 2-pyridyle. Ces composés exercent une inhibition puissance des métalloprotéases, de l'enzyme convertase du facteur de nécrose des tumeurs sans cellule, et de la libération du facteur de nécrose des tumeurs à partir des cellules. En outre, dans certains cas, ils inhibent la convertase du facteur de nécrose des tumeurs et la libération de ce facteur de nécrose des tumeurs des cellules, de préférence, jusqu'aux métalloprotéases de matrice.

  一族化合物的一般结构式（I），其中W为反向羟肟酸基团（a）; R5为氢或较低烷基; R6为（b），其中Z1为杂芳烃; 最好：R1为甲基，乙基，异丙基，正丙基或3,3,3-三氟丙基; R2为异丁基或仲丁基; R3为氢; R4为叔丁基，仲丁基，1-甲氧基-1-乙基或2-(2-吡啶基甲酰氨基)-1-乙基; R5为氢; R6为2-噻唑基或2-吡啶基。这些化合物表现出对MMP的强烈抑制作用，对无细胞TNF转化酶酶和细胞中TNF的释放，以及在某些情况下，优先于基质金属蛋白酶抑制TNF转化酶和细胞中的TNF释放。
• REVERSE HYDROXAMATE DERIVATIVES AS METALLOPROTEASE INHIBITORS
  申请人：GLAXO GROUP LIMITED

  公开号：EP1019386A1

  公开（公告）日：2000-07-19
• 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%.