N-去甲基多非利特 | 176447-94-2

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: N-去甲基多非利特
• 中文别名: 多非利特相关物质A
• 英文名称: [Cy3B]-N-Demethyldofetilide
• 英文别名: N-Demethyldofetilide；N-desmethyldofetilide；N-[4-[2-[2-[4-(methanesulfonamido)phenoxy]ethylamino]ethyl]phenyl]methanesulfonamide
• CAS: 176447-94-2
• 化学式: C₁₈H₂₅N₃O₅S₂
• 分子量: 427.546
• InChiKey: JITIJIUDNAYXKK-UHFFFAOYSA-N

物化性质

• 沸点：
  623.5±65.0 °C(Predicted)
• 密度：
  1.363±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  28
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  8

安全信息

• WGK Germany：
  3
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

反应信息

• 作为反应物：
  描述：

  N-去甲基多非利特 在 三乙酰氧基硼氢化钠 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 为溶剂， 反应 0.08h， 生成 N-[4-(2-{(6-aminohexyl)[2-(4-methanesulfonylaminophenoxy)ethyl]amino}ethyl)phenyl]methanesulfonamide trifluoroacetate
  参考文献：
  名称：

  Fluorescently Labeled Analogues of Dofetilide as High-Affinity Fluorescence Polarization Ligands for the Human Ether-a-go-go-Related Gene (hERG) Channel

  摘要：

  Novel fluorescent derivatives of dofetilide (1) have been synthesized. Analogues that feature a fluorescent probe attached through an aliphatic spacer to the central tertiary nitrogen of 1 have high affinity for the hERG channel, and affinity is dependent on both linker length and pendent dye. These variables have been optimized to generate Cy3B derivative 10e, which has hERG channel affinity equivalent to that of dofetilide. When bound to cell membranes expressing the hERG channel, 10e shows a robust increase in fluorescence polarization (FP) signal. In a FP binding assay using 10e as tracer ligand, K-i values for several known hERG channel blockers were measured and excellent agreement with the literature K-i values was observed over an affinity range of 2 nM to 3 mu M. 10e blocks hERG channel current in electrophysiological patch clamp experiments, and computational docking experiments predict that the dofetilide core of 10e binds hERG channel in a conformation similar to that previously predicted for 1. These analogues enable high-throughput hERG channel binding assays that are rapid, economical, and predictive of test compounds' potential for prolonged QT liabilities.

  DOI：

  10.1021/jm0700565
• 作为产物：
  描述：

  4-硝基苯乙胺氢溴酸盐 在 palladium on activated charcoal 盐酸 、 ammonium chloride 、 氢气 、 铁粉 、 potassium carbonate 、 溶剂黄146 、 三乙胺 作用下， 以 二氯甲烷 、 丙酮 、 乙腈 为溶剂， 反应 11.5h， 生成 N-去甲基多非利特
  参考文献：
  名称：

  New p-Methylsulfonamido Phenylethylamine Analogues as Class III Antiarrhythmic Agents:  Design, Synthesis, Biological Assay, and 3D-QSAR Analysis

  摘要：

  Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance action potential duration (APD). Using dofetilide (2) as a template of class III antiarrhythmic agents, we designed and synthesized 16 methylsulfonamido phenylethylamine analogues (4a-d and 5a-1). Pharmacological assay indicated that all of these compounds showed activity for increasing the ERP in isolated animal atrium; among them, the effective concentration of compound 4a is 1.6 x 10(-8) mol/L in increasing ERP by 10 ms, slightly less potent than that of 2, 1.1 x 10(-8) mol/L. Compound 4a also produced a slightly lower change in ERP at 10(-5) M, DeltaERP% = 17.5% (DeltaERP% = 24.0% for dofetilide). On the basis of this bioassay result, these 16 compounds together with dofetilide were investigated by the three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques of comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis (CoMSIA), and the hologram QSAR (HQSAR). The 3D-QSAR models were tested with another 11 compounds (4e-h and 5m-s) that we synthesized later. Results revealed that the CoMFA, CoMSIA, and HQSAR predicted activities for the 11 newly synthesized compounds that have a good correlation with their experimental value, r(2) = 0.943, 0.891, and 0.809 for the three QSAR models, respectively. This indicates that the 3D-QSAR models proved a good predictive ability and could describe the steric, electrostatic, and hydrophobic requirements for recognition forces of the receptor site. On the basis of these results, we designed and synthesized another eight new analogues of methanesulfonamido phenylethyamine (6a-h) according to the clues provided by the 3D-QSAR analyses. Pharmacological assay indicated that the effective concentrations of delaying the ERP by 10 ins of these newly designed compounds correlated well with the 3D-QSAR predicted values. It is remarkable that the percent change of delaying ERP at 10-5 M compound 6c is much higher than that of dofetilide; the effective concentration of compound 6c is 5.0 x 10(-8)mol/L in increasing the ERP by 10 Ms, which is slightly lower than that of 2. The results showed that the 3D-QSAR models are reliable and can be extended to design new antiarrhythmic agents.

  DOI：

  10.1021/jm010574u

文献信息

• Immediate release tablet of dofetilide
  申请人：Enaltec Pharma Research Pvt. Ltd.

  公开号：US10888524B2

  公开（公告）日：2021-01-12

  The present invention encompasses immediate release tablets of dofetilide, methods of treatment with them, as well as a process for manufacturing the same.

  本发明包括多非利特的速释片剂、使用这些片剂进行治疗的方法以及制造这些片剂的工艺。
• NOVEL POTASSIUM CHANNEL DRUGS AND THEIR USES
  申请人：Advanced Medicine, Inc.

  公开号：EP1086063A1

  公开（公告）日：2001-03-28
• EP1086063A4
  申请人：——

  公开号：EP1086063A4

  公开（公告）日：2001-03-28
• IMMEDIATE RELEASE TABLET OF DOFETILIDE
  申请人：Enaltec Pharma Research Pvt. Ltd.

  公开号：US20190240158A1

  公开（公告）日：2019-08-08

  The present invention encompasses immediate release tablets of dofetilide, methods of treatment with them, as well as a process for manufacturing the same.
• [EN] NOVEL POTASSIUM CHANNEL DRUGS AND THEIR USES<br/>[FR] MEDICAMENTS A CANAL POTASSIUM ET LEUR UTILISATION
  申请人：ADVANCED MEDICINE INC

  公开号：WO1999064050A1

  公开（公告）日：1999-12-16

  This invention relates to novel multibinding compounds that bind to potassium (K+) channels and modulate their activity. The compounds of this invention comprise 2-10 K+ channel ligands covalently connected by a linker or linkers, wherein the ligands in their monovalent (i.e., unlinked) state bind to one or more types of K+ channel. The manner of linking the ligands together is such that the multibinding agents thus formed demonstrate an increased biologic and/or therapeutic effect as compared to the same number of unlinked ligands made available for binding to the K+ channel. The invention also relates to methods of using such compounds and to methods of preparing them. The compounds of this invention are particularly useful for treating diseases and conditions of mammals that are mediated by K+ channels. Accordingly, this invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and an effective amount of a compound of this invention.