1‐(2‐(2‐hydroxy‐3‐(4‐phenylpiperidine‐1‐yl)propoxy)phenyl)‐3‐phenylpropan‐1‐one hydrochloride | 1295470-24-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 直链 1,3-二芳基丙烷
• 英文名称: 1‐(2‐(2‐hydroxy‐3‐(4‐phenylpiperidine‐1‐yl)propoxy)phenyl)‐3‐phenylpropan‐1‐one hydrochloride
• 英文别名: (+/-)-SJ312561 hydrochloride；1-[2-[2-Hydroxy-3-(4-phenylpiperidin-1-yl)propoxy]phenyl]-3-phenylpropan-1-one;hydrochloride
• CAS: 1295470-24-4
• 化学式: C₂₉H₃₃NO₃*ClH
• 分子量: 480.047
• InChiKey: IHJPRWYCRBWGGD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.54
• 重原子数：
  34
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  49.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2'-羟基-3-苯基苯丙酮 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 18.25h， 生成 1‐(2‐(2‐hydroxy‐3‐(4‐phenylpiperidine‐1‐yl)propoxy)phenyl)‐3‐phenylpropan‐1‐one hydrochloride
  参考文献：
  名称：

  Optimization of Propafenone Analogues as Antimalarial Leads

  摘要：

  Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

  DOI：

  10.1021/jm2005546

文献信息

• Propafenone analogue with additional H‐bond acceptor group shows increased inhibitory activity on P‐glycoprotein
  作者：Anna Cseke、Theresa Schwarz、Sankalp Jain、Simon Decker、Kerstin Vogl、Ernst Urban、Gerhard F. Ecker

  DOI：10.1002/ardp.201900269

  日期：2020.3

  structure–activity relationship analysis, and docking studies to investigate the role of hydrogen bond (H‐bond) donor/acceptor properties in transporter–ligand interaction. In a previous work, it has been shown that propafenone analogs with a 4‐hydroxy‐4‐piperidine moiety exhibit a generally 10‐fold higher P‐gp inhibitory activity than expected based on their lipophilicity. Here, we specifically expanded the data

  P-糖蛋白 (P-gp) 是一种依赖 ATP 的外排泵，对治疗药物的吸收、分布和排泄具有显着影响。由于 P-gp 抑制可导致药物-药物相互作用和改变药物生物利用度，因此识别与抑制相关的分子特性在药物开发中具有重要意义。在这项研究中，我们结合化学合成、体外测试、定量构效关系分析和对接研究来研究氢键 (H-bond) 供体/受体特性在转运蛋白-配体相互作用中的作用。在之前的工作中，已经表明具有 4-羟基-4-哌啶部分的普罗帕酮类似物的 P-gp 抑制活性通常比基于其亲脂性预期的高 10 倍。这里，我们通过在 4-苯基哌啶部分的第 4 位引入取代基来扩展数据集，以评估 H 键供体/受体特征在该区域的重要性。结果表明，确实有一个氢键受体，如羟基和甲氧基，通过与 Tyr310 形成氢键来增加亲和力。
• Trapping and dissociation of propafenone derivatives in HERG channels
  作者：A Windisch、EN Timin、T Schwarz、D Stork-Riedler、T Erker、GF Ecker、S Hering

  DOI：10.1111/j.1476-5381.2010.01159.x

  日期：2011.4

  determinants of propafenone derivatives that enable drug dissociation from the closed channel state. Propafenone and four derivatives with 'short' side chains were trapped in the closed channel. Five out of six bulky derivatives efficiently dissociated from the channel at rest. One propafenone derivative with a similar bulk but lacking an H-bond acceptor in this region was trapped. Correlations were

  背景和目的人类 ether-a-go-go 相关基因 (HERG) 通道抑制剂可细分为封闭通道构象中的化合物和静止时解离的其他化合物。促进静息状态从 HERG 通道解离的结构特性目前尚不清楚。一种类似小分子的普罗帕酮被有效地困在封闭的 HERG 通道构象中。本研究的目的是确定能促进普罗帕酮衍生物解离的结构部分。实验方法人类 ether-a-go-go 相关基因通道在非洲爪蟾卵母细胞中异源表达，并使用双微电极电压钳技术记录钾电流。通过 10 种具有可变侧链但保守的推定药效团的普罗帕酮衍生物从封闭中恢复，进行了分析。关键结果 我们已经确定了使药物从封闭通道状态解离的普罗帕酮衍生物的结构决定因素。普罗帕酮和四种具有“短”侧链的衍生物被困在封闭通道中。六种庞大的衍生物中有五种有效地从静止的通道中解离出来。一种具有相似体积但在该区域缺乏氢键受体的普罗帕酮衍生物被捕获。观察到分子量和通道块的开始之间以及pK(a)
• Optimization of Propafenone Analogues as Antimalarial Leads
  作者：David J. Lowes、W. Armand Guiguemde、Michele C. Connelly、Fangyi Zhu、Martina S. Sigal、Julie A. Clark、Andrew S. Lemoff、Joseph L. Derisi、Emily B. Wilson、R. Kiplin Guy

  DOI：10.1021/jm2005546

  日期：2011.11.10

  Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.