(R)-tert-butyl 8-(biphenyl-4-ylsulfonyl)-10-methyl-3-oxo-1-phenyl-2,9-dioxa-4,8-diazaundecane-7-carboxylate | 849773-56-4

• 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)-tert-butyl 8-(biphenyl-4-ylsulfonyl)-10-methyl-3-oxo-1-phenyl-2,9-dioxa-4,8-diazaundecane-7-carboxylate
• 英文别名: tert-butyl (2R)-4-(phenylmethoxycarbonylamino)-2-[(4-phenylphenyl)sulfonyl-propan-2-yloxyamino]butanoate
• CAS: 849773-56-4
• 化学式: C₃₁H₃₈N₂O₇S
• 分子量: 582.718
• InChiKey: VBKVCXAWKUENTA-MUUNZHRXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  41
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  120
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (R)-tert-butyl 8-(biphenyl-4-ylsulfonyl)-10-methyl-3-oxo-1-phenyl-2,9-dioxa-4,8-diazaundecane-7-carboxylate 在 palladium on activated charcoal N-甲基吗啉 、 氢气 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 (R)-2-[(Biphenyl-4-sulfonyl)-isopropoxy-amino]-4-{4-[3-(3-{(R)-3-[(biphenyl-4-sulfonyl)-isopropoxy-amino]-3-tert-butoxycarbonyl-propylcarbamoyl}-propylcarbamoyl)-benzoylamino]-butyrylamino}-butyric acid tert-butyl ester
  参考文献：
  名称：

  A new development of matrix metalloproteinase inhibitors: twin hydroxamic acids as potent inhibitors of MMPs

  摘要：

  Starting from the observation that the CbzNH(CH2)(2) side chain of the potent MMP-2/MMP-14 inhibitor, benzyl-(3R)-4-(hydroxyamino)-3-[isopropoxy(1,1'-biphenyl-4yl-sulfonyl)amino]-4-oxobutylcarbamate, (R)-1 lies in a hydrophobic region (S1) exposed to the solvent of the protease active site, we hypothesized that an aminoethylcarboxamido chain structurally related to that of (R)-1 might be an useful tool to bind another linker stretching out from the protein. This would be able to interact either with a enzyme region adjacent to the active site, or with other molecules of matrix metalloproteinases (MMPs), or other proteins of the extracellular matrix (ECM) that may be involved in the enzyme activation. On these basis we describe new dimeric compounds of type 2, twin hydroxamic acids, obtained by the joint of two drug entities of (R)-1 linked in PI by extendable semirigid linkers. Type 2 compounds are potentially able to undergo more complex inhibitor enzyme interactions than those occurring with monomeric compounds of type 1, thus influencing positively the potency, selectivity and/or cytotoxicity of the new compounds. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.03.002
• 作为产物：
  描述：

  2-羟基-4-苄氧羰酰氨基丁酸 在 焦磷酸硫胺素 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 8.0h， 生成 (R)-tert-butyl 8-(biphenyl-4-ylsulfonyl)-10-methyl-3-oxo-1-phenyl-2,9-dioxa-4,8-diazaundecane-7-carboxylate
  参考文献：
  名称：

  N-i-Propoxy-N-biphenylsulfonylaminobutylhydroxamic acids as potent and selective inhibitors of MMP-2 and MT1-MMP

  摘要：

  Structural manipulation of the pharmacophoric model of type A selective MMP inhibitors (MMPi), obtained by the insertion of some alkyl substituents R-2 possessing an appropriate geometry, steric bulkiness and lipophilicity, is able to improve potency, in the subnanomolar range on MMP-2, and to give a good MMP inhibition on MMP-14 (MT1-MMP) in the designed MMPi of type C, while maintaining a good MMP-1/MMP-2 selectivity profile. The simultaneous inhibition of these two enzymes yields type C compounds, which are potent antiangiogenic agents, able to block a chemoinvasion model on HUVEC cells in the micromolar range. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.01.024

文献信息

• Diagnostic agents selective against metalloproteases
  申请人：Rossello Armando

  公开号：US09480758B2

  公开（公告）日：2016-11-01

  The invention relates to aryl-sulphonamido compounds endowed with affinity against metallo proteases MMP, having formula (I) below wherein R, R1, R2, R3, G and n have the meanings reported in the specification, properly labelled with diagnostic imaging moieties or even radiotherapeutic moieties. The invention also refers to the process for their preparation, to pharmaceutical compositions comprising them and to their use as diagnostic imaging agents or radiotherapeutic agents.

  该发明涉及具有亲和力针对金属蛋白酶MMP的芳基磺胺基化合物，其具有如下式(I)中所示的结构，其中R、R1、R2、R3、G和n具有规范中报告的含义，适当地标记有诊断成像团或甚至放射治疗团。该发明还涉及它们的制备方法，包括它们的药物组合物和它们作为诊断成像剂或放射治疗剂的用途。
• ARYL-SULPHONAMIDIC DIMERS AS METALLOPROTEASES INHIBITORS
  申请人：Bracco Imaging S.p.A

  公开号：EP2149568A1

  公开（公告）日：2010-02-03

  The invention relates to dimeric aryl-sulphonamido compounds endowed with inhibitory activity against metalloproteases MMP, having formula (I) below          (M)-L-(M')     (I) wherein M and M', the same or different from each other, represent the residues of the mctalloprotcascs inhibitors of formula (II) wherein R, R1, R2, R3, G and n have the meanings reported in the specification; the invention also refers to the process for their preparation, to pharmaceutical compositions comprising them and to their use as therapeutic agents, particularly in the treatment of degenerative disorders.

  该发明涉及具有对金属蛋白酶MMP具有抑制活性的二聚芳基磺胺基化合物，其具有以下式(I)：(M)-L-(M')，其中M和M'，相同或不同，代表具有以下式(II)金属蛋白酶抑制剂的残基，其中R、R1、R2、R3、G和n在说明书中有所述；该发明还涉及其制备方法，包括它们的药物组合物以及它们作为治疗剂的用途，特别是在治疗退行性疾病方面。
• Compounds having aryl-sulphonamidic structure useful as metalloproteases inhibitors
  申请人：Bracco S.P.A.

  公开号：EP1972617A1

  公开（公告）日：2008-09-24

  The invention relates to aryl-sulphonamido compounds endowed with inhibitory activity against metallo proteases MMP, having formula (I) below wherein R, R1, R2, R3, R4, R5, n and m have the meanings reported in the specification; the invention also refers to the process for their preparation, to pharmaceutical compositions comprising them and to their use as therapeutic agents, particularly in the treatment of degenerative disorders.

  本发明涉及具有对金属蛋白酶MMP具有抑制活性的芳基磺胺基化合物，其具有以下式（I）其中R、R1、R2、R3、R4、R5、n和m具有规范中报告的含义；本发明还涉及它们的制备方法，包括它们的制药组合物以及它们作为治疗剂的用途，特别是在治疗退行性疾病方面。
• <i>N</i>-<i>O</i>-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in Vivo Antiangiogenic Activity
  作者：Elisa Nuti、Anna Rita Cantelmo、Cristina Gallo、Antonino Bruno、Barbara Bassani、Caterina Camodeca、Tiziano Tuccinardi、Laura Vera、Elisabetta Orlandini、Susanna Nencetti、Enrico A. Stura、Adriano Martinelli、Vincent Dive、Adriana Albini、Armando Rossello

  DOI：10.1021/acs.jmedchem.5b00367

  日期：2015.9.24

  Matrix metalloproteinases (MMPs) have been shown to be involved in tumor-induced angiogenesis. In particular, MMP-2, MMP-9, and MMP-14 have been reported to be crucial for tumor angiogenesis and the formation of metastasis, thus becoming attractive targets in cancer therapy. Here, we report our optimization effort to identify novel N-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward MMP-2, MMP-9, and MMP-14 with respect to the previously discovered compound 1. A new series of hydroxamates was designed, synthesized, and tested for their antiangiogenic activity using in vitro assays with human umbilical vein endothelial cells (HUVECs). A nanomolar MMP-2, MMP-9, and MMP-14 inhibitor was identified, compound 3, able to potently inhibit angiogenesis in vitro and also in vivo in the matrigel sponge assay in mice. Finally, X-ray crystallographic and docking studies were conducted for compound 3 in order to investigate its binding mode to MMP-9 and MMP-14.