(2S,4R)-2-Butyl-4-((S)-2,2-dimethyl-1-methylcarbamoyl-propylcarbamoyl)-6-(4-thiophen-3-yl-phenyl)-hexanoic acid tert-butyl ester | 187827-32-3

• 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: (2S,4R)-2-Butyl-4-((S)-2,2-dimethyl-1-methylcarbamoyl-propylcarbamoyl)-6-(4-thiophen-3-yl-phenyl)-hexanoic acid tert-butyl ester
• 英文别名: tert-butyl (2S,4R)-2-butyl-4-[[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-6-(4-thiophen-3-ylphenyl)hexanoate
• CAS: 187827-32-3
• 化学式: C₃₂H₄₈N₂O₄S
• 分子量: 556.81
• InChiKey: XFBZFGYADVTCAO-CMTIAEDTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  39
• 可旋转键数：
  16
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,4R)-2-Butyl-4-((S)-2,2-dimethyl-1-methylcarbamoyl-propylcarbamoyl)-6-(4-thiophen-3-yl-phenyl)-hexanoic acid tert-butyl ester 在 苯甲醚 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 以60 mg的产率得到(2S,4R)-2-Butyl-4-((S)-2,2-dimethyl-1-methylcarbamoyl-propylcarbamoyl)-6-(4-thiophen-3-yl-phenyl)-hexanoic acid
  参考文献：
  名称：

  Inhibition of Stromelysin-1 (MMP-3) by P₁‘-Biphenylylethyl Carboxyalkyl Dipeptides

  摘要：

  Carboxyalkyl peptides containing a biphenylylethyl group at the P-1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P-1', a tert-butyl group at P-2', and a methyl group at P-3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P-1'-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P-1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl -1,5-pentanedioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a K-i of 10 nM against MMP-3 and an ED(50) of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED(50) = 6 mg/kg iv).

  DOI：

  10.1021/jm960465t
• 作为产物：
  描述：

  4-(P-碘苯基)丁酸 在 N-甲基吗啉 、 titanium(IV) isopropylate 、 4-二甲氨基吡啶 、 N,N-二甲基丙烯基脲 、 lithium hydroxide 、 四(三苯基膦)钯 、 正丁基锂 、 四丁基氟化铵 、 双氧水 、 四氯化钛 、 碳酸氢钠 、 sodium carbonate 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 potassium bromide 、 sodium sulfite 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 19.5h， 生成 (2S,4R)-2-Butyl-4-((S)-2,2-dimethyl-1-methylcarbamoyl-propylcarbamoyl)-6-(4-thiophen-3-yl-phenyl)-hexanoic acid tert-butyl ester
  参考文献：
  名称：

  Inhibition of Stromelysin-1 (MMP-3) by P₁‘-Biphenylylethyl Carboxyalkyl Dipeptides

  摘要：

  Carboxyalkyl peptides containing a biphenylylethyl group at the P-1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P-1', a tert-butyl group at P-2', and a methyl group at P-3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P-1'-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P-1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl -1,5-pentanedioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a K-i of 10 nM against MMP-3 and an ED(50) of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED(50) = 6 mg/kg iv).

  DOI：

  10.1021/jm960465t

文献信息

• Inhibition of Stromelysin-1 (MMP-3) by P₁‘-Biphenylylethyl Carboxyalkyl Dipeptides
  作者：Craig K. Esser、Robert L. Bugianesi、Charles G. Caldwell、Kevin T. Chapman、Philippe L. Durette、Narindar N. Girotra、Ihor E. Kopka、Thomas J. Lanza、Dorothy A. Levorse、Malcolm MacCoss、Karen A. Owens、Mitree M. Ponpipom、Joseph P. Simeone、Richard K. Harrison、Lisa Niedzwiecki、Joseph W. Becker、Alice I. Marcy、Melinda G. Axel、Amy J. Christen、Joseph McDonnell、Vernon L. Moore、Julie M. Olszewski、Cheryl Saphos、Denise M. Visco、Frank Shen、Adria Colletti、Philip A. Krieter、William K. Hagmann

  DOI：10.1021/jm960465t

  日期：1997.3.1

  Carboxyalkyl peptides containing a biphenylylethyl group at the P-1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P-1', a tert-butyl group at P-2', and a methyl group at P-3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P-1'-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P-1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl -1,5-pentanedioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a K-i of 10 nM against MMP-3 and an ED(50) of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED(50) = 6 mg/kg iv).