(R)-3-[(S)-2-(1H-Indol-3-yl)-1-methylcarbamoyl-ethylcarbamoyl]-5-methyl-hexanoic acid | 171348-05-3

• 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: (R)-3-[(S)-2-(1H-Indol-3-yl)-1-methylcarbamoyl-ethylcarbamoyl]-5-methyl-hexanoic acid
• 英文别名: (3R)-3-[[(2S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl]carbamoyl]-5-methylhexanoic acid
• CAS: 171348-05-3
• 化学式: C₂₀H₂₇N₃O₄
• 分子量: 373.452
• InChiKey: YZDALJROFHNCEI-DYVFJYSZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  27
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  111
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-3-[(S)-2-(1H-Indol-3-yl)-1-methylcarbamoyl-ethylcarbamoyl]-5-methyl-hexanoic acid 在 N-甲基吗啉 、 4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐 、 肼 作用下， 以 四氢呋喃 为溶剂， 以45%的产率得到N''-{3-(R)-[2-(S)-(1H-indol-3-yl)-1-(methylcarbamoyl)-ethylcarbamoyl]-5-methylhexanoyl}-hydrazide
  参考文献：
  名称：

  Improved gelatinase a selectivity by novel zinc binding groups containing galardin derivatives

  摘要：

  The synthesis of several analogues of galardin, a MMP inhibitor, are presented with their in vitro inhibitory activity against MMP-1 and MMP-2. These compounds contain a distinct Zinc Binding Group (ZBG). Those having a 2-acylated-heterocycle as well as a 2-arylamide function do not exhibit a good inhibition/selectivity against the enzymes tested. On the contrary, those that are based on a hydrazide scaffold present potent selectivity for MMP-2 versus MMP-1. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00214-2
• 作为产物：
  描述：

  N-叔丁氧羰基-L-色氨酸 在 盐酸 、 三乙胺 、 N,N'-羰基二咪唑 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 反应 32.5h， 生成 (R)-3-[(S)-2-(1H-Indol-3-yl)-1-methylcarbamoyl-ethylcarbamoyl]-5-methyl-hexanoic acid
  参考文献：
  名称：

  Matrix Metalloproteinase Inhibitors:  A Structure−Activity Study

  摘要：

  Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1' and P3' substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.

  DOI：

  10.1021/jm970494j

文献信息

• 一种基质金属蛋白酶抑制剂及其药用用途
  申请人：复旦大学

  公开号：CN106588744B

  公开（公告）日：2019-10-08

  本发明属于药物化学和医药技术领域，涉及一种新型基质金属蛋白酶抑制剂及其药用用途。所述的抑制剂是式(1)所示的苯甲酰胺类伊洛马斯他衍生物：式(1)中，R1为包含但不限于2‑NH2，氨基被乙酰氨基取代等。R2包含但不限于氢原子，氟，氯，溴，甲基，乙基，NH2，取代氨基，甲氧基，乙氧基，三氟甲基，环己基，苯基，取代苯基，噻吩，吡咯，呋喃，噻唑，吡啶等芳香基团；R2的取代苯基包含但不限于苯环的4’位连接甲基，乙基，甲氧基，乙氧基，三氟甲基，羟基，氟，氯，溴，乙酰基，苯甲酮等基团。本发明经试验表明，所述的苯甲酰胺类伊洛马斯他衍生物可用于制备抗肝癌、肺癌、乳腺癌及卵巢癌等肿瘤的侵袭与扩散的药物。
• Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with improved selectivity
  作者：Gwennaël LeDour、Gautier Moroy、Matthieu Rouffet、Erika Bourguet、Dominique Guillaume、Martine Decarme、Haquima ElMourabit、Franck Augé、Alain J.P. Alix、Jean-Yves Laronze、Georges Bellon、William Hornebeck、Janos Sapi

  DOI：10.1016/j.bmc.2008.07.041

  日期：2008.9

  Hydrazide derivatives of Ilomastat, carrying either aryl groups or distinct alkyl and arylsulfonyl moieties were synthesized and evaluated for their MMP inhibitory activity. Potent and selective MMP-9 inhibition (IC50 = 3 nM) was observed for compound 3m (arylsulfonyl group: 4-(4-Br-C6H4)-C6H4-SO2-). Interaction with the S-2 enzyme subsite is mainly responsible for the inhibitory properties of this derivative as confirmed by molecular docking computation. (C) 2008 Elsevier Ltd. All rights reserved.
• Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis
  作者：Jiao Song、Peng Peng、Jun Chang、Ming-Ming Liu、Jian-Ming Yu、Lu Zhou、Xun Sun

  DOI：10.1016/j.bmcl.2016.03.064

  日期：2016.5

  Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against MMP-2 with IC50 value of 0.19 nM, which is 5 times more potent than that of Ilomastat (IC50 = 0.94 nM). Importantly, 10a exhibited more than 8300 fold selectivity for MMP-2 versus MMP-9 (IC50 = 1.58 mu M). Molecular docking studies showed that 10a bond to the catalytic active pocket of MMP-2 by a non-zinc-chelating mechanism which was different from that of Ilomastat. Furthermore, the invasion assay showed that 10a was effective in reducing HEY cells invasion at 84.6% in 50 mu M concentration. For 10a, the pharmacokinetic properties had been improved and especially the more desirable t(1/2z) was achieved compared with these of the lead compound Ilomastat. (C) 2016 Elsevier Ltd. All rights reserved.
• Matrix Metalloproteinase Inhibitors:  A Structure−Activity Study
  作者：Daniel E. Levy、France Lapierre、Weisheng Liang、Wenqing Ye、Christopher W. Lange、Xiaoyuan Li、Damian Grobelny、Marie Casabonne、David Tyrrell、Kevin Holme、Alex Nadzan、Richard E. Galardy

  DOI：10.1021/jm970494j

  日期：1998.1.1

  Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1' and P3' substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.
• Improved gelatinase a selectivity by novel zinc binding groups containing galardin derivatives
  作者：Franck Augé、William Hornebeck、Martine Decarme、Jean-Yves Laronze

  DOI：10.1016/s0960-894x(03)00214-2

  日期：2003.5

  The synthesis of several analogues of galardin, a MMP inhibitor, are presented with their in vitro inhibitory activity against MMP-1 and MMP-2. These compounds contain a distinct Zinc Binding Group (ZBG). Those having a 2-acylated-heterocycle as well as a 2-arylamide function do not exhibit a good inhibition/selectivity against the enzymes tested. On the contrary, those that are based on a hydrazide scaffold present potent selectivity for MMP-2 versus MMP-1. (C) 2003 Elsevier Science Ltd. All rights reserved.