1-(5-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)thieno[2,3-b]pyridin-4-yl)-4-methylpiperidine-4-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并吡啶类
• 英文名称: 1-(5-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)thieno[2,3-b]pyridin-4-yl)-4-methylpiperidine-4-carbonitrile
• 英文别名: 1-[5-[4-(Cyclopropanecarbonyl)piperazine-1-carbonyl]thieno[2,3-b]pyridin-4-yl]-4-methylpiperidine-4-carbonitrile；1-[5-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]thieno[2,3-b]pyridin-4-yl]-4-methylpiperidine-4-carbonitrile
• 化学式: C₂₃H₂₇N₅O₂S
• 分子量: 437.566
• InChiKey: ASZVVCYNJFVBQL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  109
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(5-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)thieno[2,3-b]pyridin-4-yl)-4-methylpiperidine-4-carbonitrile 、 三氟乙酸 以 水 、 乙腈 为溶剂， 生成 1-(5-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)thieno[2,3-b]pyridin-4-yl)-4-methylpiperidine-4-carbonitrile trifluoroacetate
  参考文献：
  名称：

  Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity

  摘要：

  Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g., ALDHIAI) is an important biomarker in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry optimization and biological characterization led to the identification of analogs with significantly improved enzymatic and cellular ALDH inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular thermal shift assay (CETSA), inhibited the formation of 3D spheroid cultures of OV-90 cancer cells, and potentiated the cytotoxicity of paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell line. Lead compounds also exhibit high specificity over other ALDH isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs are also highlighted.

  DOI：

  10.1021/acs.jmedchem.8b00270
• 作为产物：
  描述：

  乙基4-氯噻吩并[2,3-b]吡啶-5-羧酸酯 在 盐酸 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 1-(5-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)thieno[2,3-b]pyridin-4-yl)-4-methylpiperidine-4-carbonitrile
  参考文献：
  名称：

  Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity

  摘要：

  Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g., ALDHIAI) is an important biomarker in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry optimization and biological characterization led to the identification of analogs with significantly improved enzymatic and cellular ALDH inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular thermal shift assay (CETSA), inhibited the formation of 3D spheroid cultures of OV-90 cancer cells, and potentiated the cytotoxicity of paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell line. Lead compounds also exhibit high specificity over other ALDH isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs are also highlighted.

  DOI：

  10.1021/acs.jmedchem.8b00270

文献信息

• SUBSTITUTED QUINOLINE ANALOGS AS ALDEHYDE DEHYDROGENASE 1A1 (ALDH1A1) INHIBITORS
  申请人：The U.S.A. as represented by the Secretary, Department of Health and Human Services

  公开号：EP3704102A1

  公开（公告）日：2020-09-09
• Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity
  作者：Shyh-Ming Yang、Natalia J. Martinez、Adam Yasgar、Carina Danchik、Catrine Johansson、Yuhong Wang、Bolormaa Baljinnyam、Amy Q. Wang、Xin Xu、Pranav Shah、Dorian Cheff、Xinran S. Wang、Jacob Roth、Madhu Lal-Nag、James E. Dunford、Udo Oppermann、Vasilis Vasiliou、Anton Simeonov、Ajit Jadhav、David J. Maloney

  DOI：10.1021/acs.jmedchem.8b00270

  日期：2018.6.14

  Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g., ALDHIAI) is an important biomarker in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry optimization and biological characterization led to the identification of analogs with significantly improved enzymatic and cellular ALDH inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular thermal shift assay (CETSA), inhibited the formation of 3D spheroid cultures of OV-90 cancer cells, and potentiated the cytotoxicity of paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell line. Lead compounds also exhibit high specificity over other ALDH isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs are also highlighted.