(R)-2-(biphenyl-4-ylsulfonamido)-3-methylbutanoic acid

• 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)-2-(biphenyl-4-ylsulfonamido)-3-methylbutanoic acid
• 英文别名: N-(4-biphenylsulfonyl)-D-valine；Biphenylsulfonamide carboxylate, 2；(2R)-3-methyl-2-[(4-phenylphenyl)sulfonylamino]butanoic acid
• 化学式: C₁₇H₁₉NO₄S
• 分子量: 333.408
• InChiKey: BGKNBDGHNBOSGD-MRXNPFEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  91.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-2-(biphenyl-4-ylsulfonamido)-3-methylbutanoic acid 在 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 三乙胺 、 potassium iodide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 N-(4-biphenylsulfonyl)-N-tert-butoxycarbonylmethyl-D-valine
  参考文献：
  名称：

  Novel 1-Hydroxypiperazine-2,6-diones as New Leads in the Inhibition of Metalloproteinases

  摘要：

  New compounds containing a novel zinc-binding group (1-hydroxypiperazine-2,6-dione, HPD) have been identified as effective inhibitors of matrix metalloproteinases (MMPs), with activities in the nanomolar concentration range. That moiety seemed to bind the catalytic zinc ion of MMPs, revealing itself as a new potential substitute for the hydroxamate group in the next generation of metalloproteinase inhibitors. The X-ray crystal structure of 1b elucidated its 3D conformation and supramolecular packing in solid state. Theoretical procedures were used to investigate the binding mode of this class of compounds, within the active site of MMP13. A computational method involving docking and hybrid quantum mechanical and molecular mechanical (QM/MM) dynamic simulations was developed and applied. This study suggested that the HPD moiety binds bidentately to the catalytic zinc through its oxygen atoms. The final structure obtained will allow straightforward drug design approaches in view of further optimization and development of new MMP inhibitors bearing the HPD moiety.

  DOI：

  10.1021/jm200593b
• 作为产物：
  描述：

  D-缬氨酸叔丁基盐酸盐 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 (R)-2-(biphenyl-4-ylsulfonamido)-3-methylbutanoic acid
  参考文献：
  名称：

  Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors

  摘要：

  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.

  DOI：

  10.1016/j.bmcl.2005.10.001

文献信息

• Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors
  作者：Elisa Nuti、Doretta Cuffaro、Felicia D'Andrea、Lea Rosalia、Livia Tepshi、Marina Fabbi、Grazia Carbotti、Silvano Ferrini、Salvatore Santamaria、Caterina Camodeca、Lidia Ciccone、Elisabetta Orlandini、Susanna Nencetti、Enrico A. Stura、Vincent Dive、Armando Rossello

  DOI：10.1002/cmdc.201600235

  日期：2016.8.5

  by using the fluorimetric assay, and a crystallographic analysis was performed to characterize their binding mode. Among these glycoconjugates, a nanomolar MMP‐12 inhibitor with improved water solubility, compound 3 [(R)‐2‐(N‐(2‐(3‐(2‐acetamido‐2‐deoxy‐β‐d‐glucopyranosyl)thioureido)ethyl)biphenyl‐4‐ylsulfonamido)‐3‐methylbutanoic acid], was identified.

  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]。
• 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。
• METHOD FOR TREATING ADAMTS-5-ASSOCIATED DISEASE
  申请人：Morris Elisabeth A.

  公开号：US20080311113A1

  公开（公告）日：2008-12-18

  The present invention relates to methods of treating ADAMTS-5-associated diseases and particularly osteoarthritis comprising administering an agent capable of modulating ADMATS-5 activity to a subject afflicted with the disease. The agent is preferably a biaryl sulfonamide compound. The invention is based, in part, on the discovery that transgenic animals that do not express functional ADAMTS-5 show a reduction in the degree of osteoarthritis after the induction of osteoarthritis as compared to WT animals. Furthermore, the ADAMTS-5 transgenic animals have reduced aggrecanase activity in articular tissue as compared to WT animals. These animals are good models for ADAMTS-5-associated diseases, and for screening of drugs useful in the treatment and/or prevention of these diseases. There are no other animal models in which the deletion of the activity of a single gene is capable of abrogating the course of osteoarthritis. Accordingly, these animals also show that osteoarthritis can be prevented and/or treated by administering to a subject an ADAMTS-5 inhibitory agent and particularly an agent capable of inhibiting the aggrecanase activity of ADAMTS-5.

  本发明涉及治疗ADAMTS-5相关疾病，尤其是骨关节炎的方法，包括向患有该疾病的受试者施用能够调节ADMATS-5活性的药剂。该药剂优选为双芳基磺酰胺化合物。该发明部分基于这样的发现，即不表达功能性ADAMTS-5的转基因动物在诱导骨关节炎后与WT动物相比，显示出骨关节炎程度的降低。此外，ADAMTS-5转基因动物在关节组织中的聚集素酶活性相对于WT动物也有所降低。这些动物是ADAMTS-5相关疾病的良好模型，可用于筛选对治疗和/或预防这些疾病有用的药物。没有其他动物模型能够通过删除单个基因的活性来消除骨关节炎的进程。因此，这些动物还表明，通过向受试者施用ADAMTS-5抑制剂，尤其是能够抑制ADAMTS-5聚集素酶活性的药剂，可以预防和/或治疗骨关节炎。
• Dual Inhibitors of Matrix Metalloproteinases and Carbonic Anhydrases: Iminodiacetyl-Based Hydroxamate−Benzenesulfonamide Conjugates
  作者：Sérgio M. Marques、Elisa Nuti、Armando Rossello、Claudiu T. Supuran、Tiziano Tuccinardi、Adriano Martinelli、M. Amélia Santos

  DOI：10.1021/jm800964f

  日期：2008.12.25

  Matrix metalloproteinases (MMPs) and carbonic anhydrases (CAs) are two classes of zinc enzymes with different roles and catalytic targets, such as the degradation of most of the extracellular matrix (ECM) proteins and the regulation of the CO2/HCO3- equilibrium in the cells, respectively. Both families have isoforms which were proved to be involved in several stages of carcinogenic processes, and so the selective inhibition of these enzymes might be of interest in cancer therapy. We report herein the design, synthesis, and in vitro evaluation of a series Of Compounds possessing the iminodiacetic acid as the main backbone and two functional groups attached, namely, the hydroxamic acid and the arylsulfonamide (ArSO2NH2) moieties, to enable the inhibition of MMPs and CAs, respectively. These compounds were demonstrated to strongly inhibit both MMPs and CAs, some of them from the nanomolar to subnanomolar range. Furthermore, a docking study for MMPs was reported for the most promising compound in order to investigate its binding interactions with the different MMPs.
• A PROCESS FOR RESOLVING RACEMIC MIXTURES AND A DIASTEREOISOMERIC COMPLEX OF A RESOLVING AGENT AND AN ENANTIOMER OF INTEREST
  申请人：ABIOGEN PHARMA S.p.A.

  公开号：EP1986996A2

  公开（公告）日：2008-11-05