(R)-tert-butyl 2-(biphenyl-4-ylsulfonamido)-3-methylbutanoate | 873923-14-9

• 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 2-(biphenyl-4-ylsulfonamido)-3-methylbutanoate
• 英文别名: tert-butyl (2R)-3-methyl-2-[(4-phenylphenyl)sulfonylamino]butanoate
• CAS: 873923-14-9
• 化学式: C₂₁H₂₇NO₄S
• 分子量: 389.516
• InChiKey: CMMWOXJQPLNUEI-LJQANCHMSA-N

物化性质

• 沸点：
  509.5±60.0 °C(Predicted)
• 密度：
  1.140±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  27
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  80.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-tert-butyl 2-(biphenyl-4-ylsulfonamido)-3-methylbutanoate 在 甲醇 、 偶氮二甲酸二异丙酯 、 氨 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 为溶剂， 反应 48.0h， 生成 (2R)-3-methyl-2-(N-(((2R,3R,4S,5R,6R)-3,4-dihydroxy-5-acetamido-6-methoxytetrahydro-2H-pyran-2-yl)methyl)biphenyl-4-ylsulfonamido)butanoic acid
  参考文献：
  名称：

  Matrix metalloproteinase-12 inhibitors: synthesis, structure-activity relationships and intestinal absorption of novel sugar-based biphenylsulfonamide carboxylates

  摘要：

  MMP-12 is a validated target in pulmonary and cardiovascular diseases. The principal obstacles to clinical development of MMP-12 inhibitors are an inadequate selectivity for the target enzyme and a poor water solubility, with consequent poor oral bioavailability. We recently reported a new class of sugar-based arylsulfonamide carboxylates with a nanomolar activity for MMP-12, a good selectivity and an improved water solubility. In this study, we designed and synthesized new derivatives to characterize the structure-activity relationship (SAR) within this class of glycoconjugate inhibitors. All the new derivatives were tested on human recombinant MMP-12 and MMP-9 in order to evaluate their affinity and the selectivity for the target enzyme. Among them, the four most promising compounds were selected to assess their intestinal permeability using an ex vivo everted gut sac model. Given the high polarity and structural similarity to glucose, compound 3 was demonstrated to cross the intestinal membrane by using the facilitative GLUT2 transport.

  DOI：

  10.1016/j.bmc.2018.10.024
• 作为产物：
  描述：

  对联苯磺酰氯 在 三乙胺 作用下， 以 1,4-二氧六环 、 水 、 甲苯 为溶剂， 反应 18.0h， 生成 (R)-tert-butyl 2-(biphenyl-4-ylsulfonamido)-3-methylbutanoate
  参考文献：
  名称：

  糖基芳基磺酰胺羧酸盐作为选择性和水溶性基质金属蛋白酶-12抑制剂

  摘要：

  基质金属蛋白酶-12（MMP-12）被认为是研究选择性抑制剂的有吸引力的靶标，这些抑制剂可用于开发针对肺和心血管疾病的新疗法。在这项研究中，一个新的系列芳基磺酰胺羧酸，具有增加的亲水性从得到的缀合与β- Ñ乙酰基d -葡糖胺部分，设计并作为MMP-12选择性抑制剂合成。使用荧光测定法评估了它们对人MMP的抑制活性，并进行了晶体学分析以表征其结合模式。在这些糖缀合物中，是一种水溶性增强的纳摩尔MMP-12抑制剂，化合物3 [（R）-2-（N-（2-（3-（2-乙酰胺基-2-脱氧-β-d-吡喃葡糖基）硫脲基）乙基）联苯-4-基磺酰胺基）-3-甲基丁酸]。

  DOI：

  10.1002/cmdc.201600235

文献信息

• 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。
• Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors
  作者：Jason S. Xiang、Yonghan Hu、Thomas S. Rush、Jennifer R. Thomason、Manus Ipek、Phaik-Eng Sum、Leila Abrous、Joshua J. Sabatini、Katy Georgiadis、Erica Reifenberg、Manas Majumdar、Elisabeth A. Morris、Steve Tam

  DOI：10.1016/j.bmcl.2005.10.001

  日期：2006.1

  Aggrecanases are recently discovered enzymes that cleave aggrecan, a key component of cartilage. Aggrecanase inhibitors may provide a unique means to halt the progression of cartilage destruction in osteoarthritis. The synthesis and evaluation of biphenylsulfonamidocarboxylic acid inhibitors of aggrecanase-1 are reported. Compound 24 demonstrated 89% inhibition of proteoglycan degradation at 10 mu g/mL and has an oral bioavailability in rat of 35%. (c) 2005 Elsevier Ltd. All rights reserved.
• Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors
  作者：Stian Sjøli、Elisa Nuti、Caterina Camodeca、Irina Bilto、Armando Rossello、Jan-Olof Winberg、Ingebrigt Sylte、Olayiwola A. Adekoya

  DOI：10.1016/j.ejmech.2015.11.019

  日期：2016.1

  Enzymes of the M4 family of zinc-metalloproteinases are virulence factors secreted from gram-positive or gram-negative bacteria, and putative drug targets in the treatment of bacterial infections. In order to have a therapeutic value such inhibitors should not interfere with endogenous zinc-metalloproteinases. In the present study we have synthesised a series of hydroxamate derivatives and validated the compounds as inhibitors of the M4 enzymes thermolysin and pseudolysin, and the endogenous metalloproteinases ADAM-17, MMP-2 and MMP-9 using experimental binding studies and molecular modelling. In general, the compounds are stronger inhibitors of the MMPs than of the M4 enzymes, however, an interesting exception is LM2. The compounds bound stronger to pseudolysin than to thermolysin, and the molecular modelling studies showed that occupation of the S-2' subpocket by an aromatic group is favourable for strong interactions with pseudolysin. (C) 2015 Elsevier Masson SAS. All rights reserved.
• [EN] ARYL-SULPHONAMIDIC DIMERS AS METALLOPROTEASES INHIBITORS<br/>[FR] DIMÈRES ARYL-SULFONAMIDIQUES EN TANT QU'INHIBITEURS DE MÉTALLOPROTÉASES
  申请人：BRACCO IMAGING SPA

  公开号：WO2010010080A1

  公开（公告）日：2010-01-28

  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 metalloproteases 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.
• Matrix metalloproteinase-12 inhibitors: synthesis, structure-activity relationships and intestinal absorption of novel sugar-based biphenylsulfonamide carboxylates
  作者：Doretta Cuffaro、Caterina Camodeca、Felicia D'Andrea、Eugenia Piragine、Lara Testai、Vincenzo Calderone、Elisabetta Orlandini、Elisa Nuti、Armando Rossello

  DOI：10.1016/j.bmc.2018.10.024

  日期：2018.12

  MMP-12 is a validated target in pulmonary and cardiovascular diseases. The principal obstacles to clinical development of MMP-12 inhibitors are an inadequate selectivity for the target enzyme and a poor water solubility, with consequent poor oral bioavailability. We recently reported a new class of sugar-based arylsulfonamide carboxylates with a nanomolar activity for MMP-12, a good selectivity and an improved water solubility. In this study, we designed and synthesized new derivatives to characterize the structure-activity relationship (SAR) within this class of glycoconjugate inhibitors. All the new derivatives were tested on human recombinant MMP-12 and MMP-9 in order to evaluate their affinity and the selectivity for the target enzyme. Among them, the four most promising compounds were selected to assess their intestinal permeability using an ex vivo everted gut sac model. Given the high polarity and structural similarity to glucose, compound 3 was demonstrated to cross the intestinal membrane by using the facilitative GLUT2 transport.