4-methyl-N-methyl-N-(2-phenyl-2H-pyrazol-3-yl)benzenesulfonamide | 374632-71-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-methyl-N-methyl-N-(2-phenyl-2H-pyrazol-3-yl)benzenesulfonamide
• 英文别名: N,4-dimethyl-N-(2-phenylpyrazol-3-yl)benzenesulfonamide
• CAS: 374632-71-0
• 化学式: C₁₇H₁₇N₃O₂S
• 分子量: 327.407
• InChiKey: KRHPBWNETCEFGS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  63.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  sulfafenazole 、 碘甲烷 在 sodium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以97%的产率得到4-methyl-N-methyl-N-(2-phenyl-2H-pyrazol-3-yl)benzenesulfonamide
  参考文献：
  名称：

  Synthesis of Sulfaphenazole Derivatives and Their Use as Inhibitors and Tools for Comparing the Active Sites of Human Liver Cytochromes P450 of the 2C Subfamily

  摘要：

  Twenty-three new derivatives of sulfaphenazole (SPA) were synthesized to further explore the topology of the active sites of human liver cytochromes P450 of the 2C subfamily and to find new selective inhibitors of these cytochromes. These compounds are derived from SPA by replacement of the NH2 and H (of the SO2NH function) substituents of SPA with various R-1 and R-2 groups, respectively. Their inhibitory effects were studied on recombinant CYP 2C8, 2C9, 2C18, and 2C19 expressed in yeast. High affinities for CYP 2C9 (IC50 < 1 muM) were only observed for SPA derivatives having the SO2NH function and a relatively small R-1 substituent (R-1 = NH2, CH3). Any increase in the size of R-1 led to a moderate decrease of the affinity, and the N-alkylation of the SO2NH function of SPA to a greater decrease of this affinity. The same structural changes led to opposite effects on molecular recognition by CYP 2C8 and 2C18, which generally exhibited similar behaviors. Thus, contrary to CYP 2C9, CYP 2C8 and 2C18 generally prefer neutral compounds with relatively large R-1 and R2 substituents. CYP 2C19 showed an even lower affinity for anionic compounds than CYP 2C8 and 2C18. However, as CYP 2C8 and 2C18, CYP 2C19 showed a much better affinity for neutral compounds derived ftom N-alkylation of SPA and for anionic compounds bearing a larger R, substituent. One of the new compounds (R-1 = methyl, R-2 = propyl) inhibited all human CYP 2Cs with IC50 values between 10 and 20 muM, while another one (R-1 = allyl, R-2 = methyl) inhibited all CYP 2Cs except CYP 2C9, and a third one (R-1 = R-2 = methyl) inhibited all CYP 2Cs except CYP 2C8. Only 2 compounds of the 25 tested derivatives were highly selective toward one human CYP 2C; these are SPA and compound I (Ri = CH3, R2 = H), which acted as selective CYP 2C9 inhibitors. However, some SPA derivatives selectively inhibited CYP 2C8 and 2C18. Since CYP 2C18 is hardly detectable in human liver, these derivatives could be interesting molecules to selectively inhibit CYP 2C8 in human liver microsomes. Thus, compound 11 (R-1 = NH2, R-2 = (CH2)(2)CH(CH3)(2)) appears to be particularly interesting for that purpose as its IC50 value for CYP 2C8 is low (3 muM) and 20-fold smaller than those found for CYP 2C9 and 2C19.

  DOI：

  10.1021/jm010861y

文献信息

• 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。
• US8793078B2
  申请人：——

  公开号：US8793078B2

  公开（公告）日：2014-07-29
• [EN] METHOD FOR PREDICTING ACTIVATION ENERGY USING AN ATOMIC FINGERPRINT DESCRIPTOR OR AN ATOMIC DESCRIPTOR<br/>[FR] PROCÉDÉ DE PRÉDICTION D'ÉNERGIE D'ACTIVATION AU MOYEN D'UN DESCRIPTEUR D'EMPREINTE ATOMIQUE OU D'UN DESCRIPTEUR ATOMIQUE
  申请人：BIOINFORMATICS & MOLECULAR DES

  公开号：WO2010056053A2

  公开（公告）日：2010-05-20

  본 발명은 원자 지문 표현자의 데이터베이스를 구축하는 방법을 제공한다. 또한, (i) 기질의 원자 지문 표현자(atomic fingerprint descriptor)를 계산하는 단계; (ii) 상기 방법으로 구축된 데이터와 비교하여 사이토크롬 P450 효소에 의한 대사반응이 가능한 원자 위치를 선별하는 단계; 및 (iii) 선별한 원자 위치에 대하여 원자 표현자(atomic descriptor)를 이용하여 활성화 에너지를 예측하는 단계를 포함하는, 원자 지문 표현자 및 원자 표현자를 이용하여 활성화 에너지를 예측하는 방법을 제공한다. 또한, 본 발명은 효과적인 원자 표현자를 이용하여 CYP450 효소에 의해 이뤄지는 1단계(phase I) 대사의 활성화에너지를 예측하는 방법을 제공한다. 구체적으로, 본 발명은 효과적인 원자 표현자를 포함한 방정식을 이용하여 사이토크롬 P450 효소에 의한 수소분리반응 또는 방향족 수산화반응의 4면체 중간체 형성의 활성화에너지를 예측하는 방법을 제공한다. 본 발명의 방법은 어떤 추가적인 CYP450과 기질의 도킹실험이나 양자역학적 계산이 없이 실용적 수준으로까지 1 단계(Phase I) 대사체들에 대해 빠르게 예측해 줌으로서 컴퓨터를 이용한 신약개발을 훨씬 더 용이하게 하고, 약물의 대사반응가능성 분석을 통한 대사체 회피설계를 통하여 약물의 생체이용률(bioavailability)를 증가시키는데 전략을 제시할 수 있다. 또한, 본 발명의 활성화 에너지 예측을 통하여 i) 대사 산물, ii) 대사의 상대적인 속도, iii) 대사의 위치선택성, iv) 대사의 저해, v) 약물 간 상호작용, 및 vi) 대사체의 독성을 예측할 수 있다.
• Synthesis of Sulfaphenazole Derivatives and Their Use as Inhibitors and Tools for Comparing the Active Sites of Human Liver Cytochromes P450 of the 2C Subfamily
  作者：Nguyêt-Thanh Ha-Duong、Sylvie Dijols、Cristina Marques-Soares、Claire Minoletti、Patrick M. Dansette、Daniel Mansuy

  DOI：10.1021/jm010861y

  日期：2001.10.1

  Twenty-three new derivatives of sulfaphenazole (SPA) were synthesized to further explore the topology of the active sites of human liver cytochromes P450 of the 2C subfamily and to find new selective inhibitors of these cytochromes. These compounds are derived from SPA by replacement of the NH2 and H (of the SO2NH function) substituents of SPA with various R-1 and R-2 groups, respectively. Their inhibitory effects were studied on recombinant CYP 2C8, 2C9, 2C18, and 2C19 expressed in yeast. High affinities for CYP 2C9 (IC50 < 1 muM) were only observed for SPA derivatives having the SO2NH function and a relatively small R-1 substituent (R-1 = NH2, CH3). Any increase in the size of R-1 led to a moderate decrease of the affinity, and the N-alkylation of the SO2NH function of SPA to a greater decrease of this affinity. The same structural changes led to opposite effects on molecular recognition by CYP 2C8 and 2C18, which generally exhibited similar behaviors. Thus, contrary to CYP 2C9, CYP 2C8 and 2C18 generally prefer neutral compounds with relatively large R-1 and R2 substituents. CYP 2C19 showed an even lower affinity for anionic compounds than CYP 2C8 and 2C18. However, as CYP 2C8 and 2C18, CYP 2C19 showed a much better affinity for neutral compounds derived ftom N-alkylation of SPA and for anionic compounds bearing a larger R, substituent. One of the new compounds (R-1 = methyl, R-2 = propyl) inhibited all human CYP 2Cs with IC50 values between 10 and 20 muM, while another one (R-1 = allyl, R-2 = methyl) inhibited all CYP 2Cs except CYP 2C9, and a third one (R-1 = R-2 = methyl) inhibited all CYP 2Cs except CYP 2C8. Only 2 compounds of the 25 tested derivatives were highly selective toward one human CYP 2C; these are SPA and compound I (Ri = CH3, R2 = H), which acted as selective CYP 2C9 inhibitors. However, some SPA derivatives selectively inhibited CYP 2C8 and 2C18. Since CYP 2C18 is hardly detectable in human liver, these derivatives could be interesting molecules to selectively inhibit CYP 2C8 in human liver microsomes. Thus, compound 11 (R-1 = NH2, R-2 = (CH2)(2)CH(CH3)(2)) appears to be particularly interesting for that purpose as its IC50 value for CYP 2C8 is low (3 muM) and 20-fold smaller than those found for CYP 2C9 and 2C19.