(2R)-3-(3-(3-bromobenzyl)-3-(3-(trifluoromethoxy)phenyl)indolin-1-yl)-1,1,1-trifluoropropan-2-ol

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (2R)-3-(3-(3-bromobenzyl)-3-(3-(trifluoromethoxy)phenyl)indolin-1-yl)-1,1,1-trifluoropropan-2-ol
• 英文别名: (2R)-3-[3-[(3-bromophenyl)methyl]-3-[3-(trifluoromethoxy)phenyl]-2H-indol-1-yl]-1,1,1-trifluoropropan-2-ol
• 化学式: C₂₅H₂₀BrF₆NO₂
• 分子量: 560.334
• InChiKey: HHZMLPGJLZQHHG-WTQRLHSKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.9
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  32.7
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2R)-3-(3-(3-bromobenzyl)-3-(3-(trifluoromethoxy)phenyl)indolin-1-yl)-1,1,1-trifluoropropan-2-ol 在 水 、 palladium diacetate 、 三乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 sodium hydroxide 作用下， 75.0 ℃ 、137.9 kPa 条件下， 反应 12.0h， 生成 3-((1-((R)-3,3,3-trifluoro-2-hydroxypropyl)-3-(3-(trifluoromethoxy)phenyl)indolin-3-yl)methyl)benzoic acid
  参考文献：
  名称：

  Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach

  摘要：

  Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharinacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from H-1 NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.

  DOI：

  10.1021/acsmedchemlett.5b00404
• 作为产物：
  描述：

  3-三氟甲氧基溴苯 在 tris-(dibenzylideneacetone)dipalladium(0) 、 硼烷四氢呋喃络合物 、 potassium carbonate 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 四氢呋喃 、 N,N-二甲基乙酰胺 为溶剂， 反应 54.0h， 生成 (2R)-3-(3-(3-bromobenzyl)-3-(3-(trifluoromethoxy)phenyl)indolin-1-yl)-1,1,1-trifluoropropan-2-ol
  参考文献：
  名称：

  Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach

  摘要：

  Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharinacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from H-1 NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.

  DOI：

  10.1021/acsmedchemlett.5b00404

文献信息

• [EN] 3,3'-DISUBSTITUTED INDOLINES AS INHIBITORS OF CHOLESTEROL ESTER TRANSFER PROTEIN<br/>[FR] INDOLINES 3,3'-DISUBSTITUÉES UTILISÉES COMME INHIBITEURS DE LA PROTÉINE DE TRANSFERT DU CHOLESTÉROL ESTÉRIFIÉ
  申请人：MERCK SHARP & DOHME

  公开号：WO2015054088A1

  公开（公告）日：2015-04-16

  3,3'-Disubstituted indoline compounds, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis.

  3,3'-二取代吲哚化合物，包括该化合物的药用盐，是CETP抑制剂，可用于提高HDL胆固醇，降低LDL胆固醇，并用于治疗或预防动脉粥样硬化。
• 3,3'-DISUBSTITUTED INDOLINES AS INHIBITORS OF CHOLESTEROL ESTER TRANSFER PROTEIN
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP3054945A1

  公开（公告）日：2016-08-17
• US9688630B2
  申请人：——

  公开号：US9688630B2

  公开（公告）日：2017-06-27
• Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach
  作者：Jonathan E. Wilson、Ravi Kurukulasuriya、Mikhail Reibarkh、Maud Reiter、Aaron Zwicker、Kake Zhao、Fengqi Zhang、Rajan Anand、Vincent J. Colandrea、Anne-Marie Cumiskey、Alejandro Crespo、Ruth A. Duffy、Beth Ann Murphy、Kaushik Mitra、Douglas G. Johns、Joseph L. Duffy、Petr Vachal

  DOI：10.1021/acsmedchemlett.5b00404

  日期：2016.3.10

  Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharinacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from H-1 NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.