DRF-4367 | 304647-55-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: DRF-4367
• 英文别名: Unii-ywx923E9LD；2-(hydroxymethyl)-4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide
• CAS: 304647-55-0
• 化学式: C₁₈H₁₆F₃N₃O₄S
• 分子量: 427.404
• InChiKey: MVZNVBXATDCMMJ-UHFFFAOYSA-N

物化性质

• 熔点：
  188-189 °C
• 沸点：
  624.4±65.0 °C(Predicted)
• 密度：
  1.49±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  9

ADMET

代谢

DRF_4367 已知的人类代谢物包括 2-(羟甲基)-4-[3-(三氟甲基)-5-(4-羟基苯基)-1H-吡唑-1-基]苯磺酰胺。

DRF_4367 has known human metabolites that include 2-(Hydroxymethyl)-4-[3-(trifluoromethyl)-5-(4-hydroxyphenyl)-1H-pyrazole-1-yl]benzenesulfonamide.

来源:NORMAN Suspect List Exchange

反应信息

• 作为反应物：
  描述：

  DRF-4367 在 碳酸氢钠 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 N-acetyl-2-hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethylpyrazol-1-yl]benzenesulfonamide sodium salt
  参考文献：
  名称：

  鉴定2-羟基甲基-4- [5-（4-甲氧基苯基）-3-三氟甲基-吡唑-1-基] -N-丙基苯磺酰胺钠作为口服和胃肠外给药的潜在COX-2抑制剂。

  摘要：

  描述了涉及氨磺酰基（SO（2）NH（2））和羟甲基（CH（2）OH）基团的口服活性COX-2抑制剂3的前药的合成，及其生物学评估。在这些前药中，由于全身循环中的药物水平高度升高，在角叉菜胶诱导的大鼠爪水肿模型中，发现N-丙酰磺酰胺钠3k远远优于母体化合物3和其他市售的COX-2抑制剂。由于令人印象深刻的止痛活性，退热作用和非凡的水溶性，该前药具有口服和肠胃外给药的潜力。

  DOI：

  10.1016/j.bmc.2006.08.024
• 作为产物：
  描述：

  对甲氧基苯乙酮 在 盐酸 、 sodium hydride 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 1.0h， 生成 DRF-4367
  参考文献：
  名称：

  2-Hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide (DRF-4367): an orally active COX-2 inhibitor identified through pharmacophoric modulation

  摘要：

  在N1位含有新颖药效团的1,5-二芳基吡唑类类似物被设计、合成并对体外环氧合酶（COX-1/COX-2）抑制活性进行了评估。在C-5苯环的4位及其周围的变异与C-3位的CF3和CHF2基团结合，展现出高度的效力和选择性指数（SI），用于COX-2抑制。这些强效化合物的体内评估与先前的一些化合物相比，显示4-OMe-苯基类似物6和4-NHMe-苯基类似物9（C-3位含CF3），以及4-OEt-苯基类似物19（C-3位含CHF2）对COX-2的抑制效力超过了塞来昔布。除了出色的抗炎、解热、镇痛和抗关节炎特性外，化合物6（DRF-4367）被发现具有优秀的药代动力学特性，长期关节炎研究中的胃肠道安全性，以及在人体全血检测中的COX-2效力。因此，化合物6被选为口服活性的抗炎候选物进行临床前评估。

  DOI：

  10.1039/b402787f

文献信息

• 2-Hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide (DRF-4367): an orally active COX-2 inhibitor identified through pharmacophoric modulation
  作者：Sunil Kumar Singh、Saibaba Vobbalareddy、Srinivasa Rao Kalleda、Shaikh Abdul Rajjak、Seshagiri Rao Casturi、Srinivasa Raju Datla、Rao N. V. S. Mamidi、Ramesh Mullangi、Ravikanth Bhamidipati、Rajagopalan Ramanujam、Venkateswarlu Akella、Koteswar Rao Yeleswarapu

  DOI：10.1039/b402787f

  日期：——

  Analogs of 1,5-diarylpyrazoles with a novel pharmacophore at N1 were designed, synthesized and evaluated for the in-vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The variations at/around position-4 of the C-5 phenyl ring in conjunction with a CF3 and CHF2 groups at C-3 exhibited a high degree of potency and selectivity index (SI) for COX-2 inhibition. The in-vivo evaluation of these potent compounds with a few earlier ones indicated the 4-OMe-phenyl analog 6 and the 4-NHMe-phenyl analog 9 with a CF3, and the 4-OEt-phenyl analog 19 with a CHF2 group at C-3 to possess superior potency than celecoxib. In addition to its impressive anti-inflammatory, antipyretic, analgesic and anti-arthritic properties, compound 6 (DRF-4367) was found to possess an excellent pharmacokinetic profile, gastrointestinal (GI) safety in the long-term arthritis study and COX-2 potency in human whole blood assay. Thus, compound 6 was selected as an orally active anti-inflammatory candidate for pre-clinical evaluation.

  在N1位含有新颖药效团的1,5-二芳基吡唑类类似物被设计、合成并对体外环氧合酶（COX-1/COX-2）抑制活性进行了评估。在C-5苯环的4位及其周围的变异与C-3位的CF3和CHF2基团结合，展现出高度的效力和选择性指数（SI），用于COX-2抑制。这些强效化合物的体内评估与先前的一些化合物相比，显示4-OMe-苯基类似物6和4-NHMe-苯基类似物9（C-3位含CF3），以及4-OEt-苯基类似物19（C-3位含CHF2）对COX-2的抑制效力超过了塞来昔布。除了出色的抗炎、解热、镇痛和抗关节炎特性外，化合物6（DRF-4367）被发现具有优秀的药代动力学特性，长期关节炎研究中的胃肠道安全性，以及在人体全血检测中的COX-2效力。因此，化合物6被选为口服活性的抗炎候选物进行临床前评估。
• [EN] PYRAZOLES HAVING ANTIINFLAMMATORY ACTIVITY<br/>[FR] PYRAZOLES PRESENTANT UNE ACTIVITE ANTI-INFLAMMATOIRE
  申请人：REDDY RESEARCH FOUNDATION

  公开号：WO2000066562A1

  公开（公告）日：2000-11-09

  The present invention relates to novel antiinflammatory compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel heterocyclic compounds of general the formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.

  本发明涉及新型抗炎化合物、它们的衍生物、类似物、互变异构体、立体异构体、区域异构体、多晶形态、药学上可接受的盐、药学上可接受的溶剂化合物以及含有它们的药学上可接受的组合物。更具体地说，本发明涉及一般式（I）的新型杂环化合物、它们的衍生物、类似物、互变异构体、立体异构体、区域异构体、多晶形态、药学上可接受的盐、药学上可接受的溶剂化合物以及含有它们的药学上可接受的组合物。
• METHOD FOR PREDICTING ACTIVATION ENERGY USING AN ATOMIC FINGERPRINT DESCRIPTOR OR AN ATOMIC DESCRIPTOR
  申请人：Bioinformatics&Molecular Design Research Center

  公开号：EP2354987A2

  公开（公告）日：2011-08-10

  The present invention provides a method for constructing a database of atomic fingerprint descriptors. The invention provides a method for predicting activation energy using an atomic fingerprint descriptor and an atomic descriptor, the method comprising the steps of: (i) calculating the atomic fingerprint descriptor of a substrate; (ii) comparing the calculated atomic fingerprint descriptor with the constructed atomic fingerprint descriptor database to select an atomic position where cytochrome P450-mediated metabolism occurs; and (iii) predicting activation energy for the selected atomic position using an atomic descriptor. Also, the invention provides a method of predicting the activation energy of CYP450-mediated phase I metabolism using effective atomic descriptors. Specifically, the invention provides a method of predicting the activation energy either for cytochrome P450-mediated hydrogen abstraction or for tetrahedral intermediate formation in cytochrome P450-aromatic hydroxylation using equations including effective atomic descriptors. The method of the invention can rapidly predict activation energy for phase I metabolites at a practical level without having to perform a docking experiment between any additional CYP450 and the substrate, or a quantum mechanical calculation, thereby making it easier to develop new drugs using a computer. Also, the present invention may propose a strategy for increasing the bioavailability of drugs through the avoidance of metabolites based on the possibility of drug metabolism. Furthermore, the method of the present invention proposes new empirical approaches which can also be easily applied to activation energies for various chemical reactions, and makes it possible to explain physical and chemical factors that determine activation energy. In addition, through the prediction of activation energy according to the present invention, it is possible to predict i) metabolic products, ii) the relative rate of metabolism, iii) metabolic regioselectivity, iv) metabolic inhibition, v) drug-drug interactions, and vi) the toxicity of a metabolite.

  本发明提供了一种构建原子指纹描述符数据库的方法。本发明提供了一种使用原子指纹描述符和原子描述符预测活化能的方法，该方法包括以下步骤：(i) 计算底物的原子指纹描述符；(ii) 将计算的原子指纹描述符与构建的原子指纹描述符数据库进行比较，以选择细胞色素 P450 介导的代谢发生的原子位置；以及 (iii) 使用原子描述符预测所选原子位置的活化能。此外，本发明还提供了一种利用有效原子描述符预测 CYP450 介导的 I 期代谢活化能的方法。具体来说，本发明提供了一种利用包括有效原子描述符的方程预测细胞色素 P450 介导的氢抽取活化能或细胞色素 P450 芳烃羟化四面体中间体形成活化能的方法。本发明的方法可以在实用水平上快速预测 I 期代谢物的活化能，而无需在任何额外的 CYP450 和底物之间进行对接实验，也无需进行量子力学计算，从而使使用计算机开发新药物变得更加容易。同时，本发明还可以根据药物代谢的可能性，提出一种通过避免代谢物来提高药物生物利用度的策略。此外，本发明的方法提出了新的经验方法，也可以很容易地应用于各种化学反应的活化能，并使解释决定活化能的物理和化学因素成为可能。此外，根据本发明预测活化能，还可以预测 i) 代谢产物；ii) 代谢的相对速率；iii) 代谢的区域选择性；iv) 代谢抑制；v) 药物与药物之间的相互作用；以及 vi) 代谢产物的毒性。
• Polar substitutions in the benzenesulfonamide ring of celecoxib afford a potent 1,5-diarylpyrazole class of COX-2 inhibitors
  作者：Sunil K. Singh、P.Ganapati Reddy、K.Srinivasa Rao、Braj B. Lohray、P. Misra、Shaikh A. Rajjak、Yeleswarapu K. Rao、A. Venkateswarlu

  DOI：10.1016/j.bmcl.2003.10.027

  日期：2004.1

  Several chemical modifications in the N-1-benzenesulfonamide ring of celecoxib are presented. The series with a hydroxymethyl group adjacent to the sulfonamide was found to be the most potent modification that yielded many compounds selectively active against COX-2 enzyme in vitro. (C) 2003 Elsevier Ltd. All rights reserved.
• NOVEL COMPOSITION FOR TREATING METABOLIC SYNDROME AND OTHER CONDITIONS
  申请人：Chen Chien-Hung

  公开号：US20120183600A1

  公开（公告）日：2012-07-19

  The invention relates to a composition that includes a first agent selected from the group consisting of an oxidative phosphorylation inhibitor, an ionophore, and an adenosine 5′-monophosphate-activated protein kinase (AMPK) activator; a second agent that possesses anti-inflammatory activity; and a third agent that possesses serotonin activity.