2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-3-methoxyphenyl)acetic acid | 1080520-82-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-3-methoxyphenyl)acetic acid
• 英文别名: 2-[4-[[4-[(2,4-dichlorophenyl)sulfonylamino]-2-methyl-1H-indol-5-yl]oxy]-3-methoxyphenyl]acetic acid
• CAS: 1080520-82-6
• 化学式: C₂₄H₂₀Cl₂N₂O₆S
• 分子量: 535.405
• InChiKey: BSPMBSFCVOLGHL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  126
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-3-methoxyphenyl)acetic acid 在 N-氯代丁二酰亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以45%的产率得到2-(4-(3-chloro-4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-3-methoxyphenyl)acetic acid
  参考文献：
  名称：

  Solving time-dependent CYP3A4 inhibition for a series of indole-phenylacetic acid dual antagonists of the PGD2 receptors CRTH2 and DP

  摘要：

  Based on their structural similarity to previously described compound AMG 009, indole-phenyl acetic acids were proposed to be potent dual inhibitors of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2) and prostanoid D receptor (DP or DP1). This series was equipotent to AMG 009 in binding assays against both receptors but exhibited decreased serum shift. We discovered early in the optimization of these indole-phenylacetic acid compounds that they demonstrated CYP3A4 time-dependent inhibition (TDI). Hypothesizing that the source of TDI was the indole core we modified the 1,2,3-substitution to eventually afford a highly potent modulator of CRTH2 and DP which did not exhibit TDI. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.04.092
• 作为产物：
  描述：

  高香草酸 在 吡啶 、 lithium hydroxide 、 potassium tert-butylate 、 水 、 caesium carbonate 、 tin(ll) chloride 作用下， 以 甲醇 、 水 、 二甲基亚砜 为溶剂， 反应 33.5h， 生成 2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-3-methoxyphenyl)acetic acid
  参考文献：
  名称：

  WO2008/137027

  摘要：

  公开号：

文献信息

• Bioactivation of a Novel 2-Methylindole-Containing Dual Chemoattractant Receptor-Homologous Molecule Expressed on T-Helper Type-2 Cells/d-Prostanoid Receptor Antagonist Leads to Mechanism-Based CYP3A Inactivation: Glutathione Adduct Characterization and Prediction of In Vivo Drug-Drug Interaction
  作者：Simon G. Wong、Peter W. Fan、Raju Subramanian、George R. Tonn、Kirk R. Henne、Michael G. Johnson、Michelle Tadano Lohr、Bradley K. Wong

  DOI：10.1124/dmd.109.031344

  日期：2010.5

  The 2-methyl substituted indole, 2MI [2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1 H -indol-5-yloxy)-3-methoxyphenyl)acetic acid] is a potent dual inhibitor of 1) chemoattractant receptor-homologous molecule expressed on T-helper type-2 cells and 2) d-prostanoid receptor. During evaluation as a potential treatment for asthma and allergic rhinitis, 2MI was identified as a mechanism-based inactivator of CYP3A4 in vitro. The inactivation was shown to be irreversible by dialysis and accompanied by an NADPH-dependent increase in 2MI covalent binding to a 55- to 60-kDa microsomal protein, consistent with irreversible binding to CYP3A4. Two glutathione (GSH) adducts, G1 and G2, were identified in vitro, and the more abundant adduct (G1) was unambiguously determined via NMR to be GSH adducted to the 3-position of the 2-methylindole moiety. The potential for a clinical drug-drug interaction arising from mechanism-based inactivation of CYP3A4 by 2MI was predicted using a steady-state model, and a 4.3- to 7.5-fold increase in the exposure of midazolam was predicted at anticipated therapeutic concentrations. To better assess the potential for in vivo drug-drug interactions, the Sprague-Dawley rat was used as an in vivo model. An excellent in vitro-in vivo correlation was observed for the reduction in enzyme steady-state concentration ( E′ ss/ E ss) as well as the change in the exposure of a prototypical CYP3A substrate, indinavir (area under the curve (AUC) for indinavir/AUC). In summary, 2MI was identified as a potent mechanism-based inactivator of CYP3A and was predicted to elicit a clinically relevant drug-drug interaction in humans at an anticipated therapeutic concentration.

  2-甲基取代的吲哚，2MI [2-(4-(4-(2,4-二氯苯基磺酰胺基)-2-甲基-1 H-吲哚-5-基氧基)-3-甲氧基苯基)乙酸]是一种有效的双1) 2 型 T 辅助细胞上表达的趋化剂受体同源分子和 2) d-前列腺素受体的抑制剂。在评估其作为哮喘和过敏性鼻炎的潜在治疗方法时，2MI 被确定为体外基于机制的 CYP3A4 灭活剂。该失活被证明是通过透析不可逆的，并且伴随着与 55-至 60-kDa 微粒体蛋白的 2MI 共价结合的 NADPH 依赖性增加，这与与 CYP3A4 的不可逆结合一致。在体外鉴定了两种谷胱甘肽 (GSH) 加合物，G1 和 G2，并且通过 NMR 明确确定更丰富的加合物 (G1) 是加成到 2-甲基吲哚部分 3 位的 GSH。使用稳态模型预测了 2MI 基于机制的 CYP3A4 失活引起的临床药物相互作用的可能性，并预测在预期治疗浓度下咪达唑仑的暴露量会增加 4.3 至 7.5 倍。为了更好地评估体内药物相互作用的潜力，使用 Sprague-Dawley 大鼠作为体内模型。酶稳态浓度 (E' ss/ E ss) 的降低以及原型 CYP3A 底物茚地那韦暴露量的变化（曲线下面积 (AUC)）观察到良好的体外-体内相关性对于茚地那韦/AUC）。总之，2MI 被确定为一种有效的基于机制的 CYP3A 灭活剂，预计在预期的治疗浓度下会在人体中引发临床相关的药物间相互作用。
• COMPOUNDS AND METHODS USEFUL FOR TREATING ASTHMA AND ALLERGIC INFLAMMATION
  申请人：Brown Matthew

  公开号：US20080312270A1

  公开（公告）日：2008-12-18

  Compounds, compositions and methods that are useful in the treatment of inflammatory and immune-related diseases and conditions are provided herein. In particular, the invention provides compounds which modulate the function and/or expression of proteins involved in atopic diseases, inflammatory conditions and cancer. The subject compounds are carboxylic acid derivatives.

  本文提供了在治疗炎症和免疫相关疾病和病况方面有用的化合物、组合物和方法。具体而言，本发明提供了调节参与过敏性疾病、炎症病症和癌症的蛋白质的功能和/或表达的化合物。所述化合物为羧酸衍生物。
• Compounds and methods useful for treating asthma and allergic inflammation
  申请人：Amgen Inc.

  公开号：US07960567B2

  公开（公告）日：2011-06-14

  Compounds, compositions and methods that are useful in the treatment of inflammatory and immune-related diseases and conditions are provided herein. In particular, the invention provides compounds which modulate the function and/or expression of proteins involved in atopic diseases, inflammatory conditions and cancer. The subject compounds are carboxylic acid derivatives.

  本文提供了用于治疗炎症和免疫相关疾病和病况的化合物、组合物和方法。特别地，本发明提供了调节参与特应性疾病、炎症病况和癌症的蛋白质的功能和/或表达的化合物。这些化合物是羧酸衍生物。
• COMPOUNDS AS CRTH2 AND/OR PGD2 RECEPTORS MODULATORS AND THEIR USE FOR TREATING ASTHMA AND ALLERGIC INFLAMMATION
  申请人：Amgen Inc.

  公开号：EP2164828A2

  公开（公告）日：2010-03-24
• US7960567B2
  申请人：——

  公开号：US7960567B2

  公开（公告）日：2011-06-14