4-[(1-methyl-4-phenylmethoxyindol-3-yl)methylidene]-3-thiophen-2-yl-1H-pyrazol-5-one | 1352136-43-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 4-[(1-methyl-4-phenylmethoxyindol-3-yl)methylidene]-3-thiophen-2-yl-1H-pyrazol-5-one
• CAS: 1352136-43-6
• 化学式: C₂₄H₁₉N₃O₂S
• 分子量: 413.5
• InChiKey: ZDHKUEIMKDKNET-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.74
• 重原子数：
  30.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  55.62
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  1-甲基-4-苯基甲氧基吲哚-3-甲醛 、 5-(thiophen-2-yl)-2,4-dihydro-3H-pyrazol-3-one 在 哌啶 作用下， 以 乙醇 为溶剂， 生成 4-[(1-methyl-4-phenylmethoxyindol-3-yl)methylidene]-3-thiophen-2-yl-1H-pyrazol-5-one
  参考文献：
  名称：

  Pyrazolone-based anaplastic lymphoma kinase (ALK) inhibitors: Control of selectivity by a benzyloxy group

  摘要：

  Anaplastic lymphoma kinase (ALK) is transmembrane receptor tyrosine kinase, with oncogenic variants that have been implicated in ALCL, NSCLC and other cancers. Screening of a VEGFR2-biased kinase library resulted in identification of 1 which showed cross-reactivity with ALK. SAR on the indole segment of 1 showed that a subtle structural modification (the ethoxy group of 1 changed to a benzyloxy to generate 5a) enhanced potency (ALK), selectivity for VEGFR2 and IR along with improvement in metabolic stability. From docking studies of ALK versus VEGFR2 kinase, we postulated that the loss of entropy of the VEGFR2 in the bound form with 5a might be the origin of the reduced activity against that protein. Modification of the heterocyclic segment showed that thiazole-bearing pyrazolones preserved enzyme potency, and enhanced inhibition of NPM-ALK autophosphorylation in ALK-positive ALCL cells (Karpas-299). SAR of the benzyloxy group resulted in compounds which demonstrated good cellular potency in Karpas-299 cells. Compound 8 showed best overall profile for the series with broad kinome selectivity and liver micorsome stability. Compound 8 showed reasonable iv PK in rat, but with little oral exposure. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.10.055

文献信息

• Pyrazolone-based anaplastic lymphoma kinase (ALK) inhibitors: Control of selectivity by a benzyloxy group
  作者：Rabindranath Tripathy、Robert J. McHugh、Arup K. Ghose、Gregory R. Ott、Thelma S. Angeles、Mark S. Albom、Zeck Huang、Lisa D. Aimone、Mangeng Cheng、Bruce D. Dorsey

  DOI：10.1016/j.bmcl.2011.10.055

  日期：2011.12

  Anaplastic lymphoma kinase (ALK) is transmembrane receptor tyrosine kinase, with oncogenic variants that have been implicated in ALCL, NSCLC and other cancers. Screening of a VEGFR2-biased kinase library resulted in identification of 1 which showed cross-reactivity with ALK. SAR on the indole segment of 1 showed that a subtle structural modification (the ethoxy group of 1 changed to a benzyloxy to generate 5a) enhanced potency (ALK), selectivity for VEGFR2 and IR along with improvement in metabolic stability. From docking studies of ALK versus VEGFR2 kinase, we postulated that the loss of entropy of the VEGFR2 in the bound form with 5a might be the origin of the reduced activity against that protein. Modification of the heterocyclic segment showed that thiazole-bearing pyrazolones preserved enzyme potency, and enhanced inhibition of NPM-ALK autophosphorylation in ALK-positive ALCL cells (Karpas-299). SAR of the benzyloxy group resulted in compounds which demonstrated good cellular potency in Karpas-299 cells. Compound 8 showed best overall profile for the series with broad kinome selectivity and liver micorsome stability. Compound 8 showed reasonable iv PK in rat, but with little oral exposure. (C) 2011 Elsevier Ltd. All rights reserved.