8-环戊基-7,8-二氢-2-[[4-(4-甲基-1-哌嗪基)苯基]氨基]-7-氧代-吡啶并[2,3-d]嘧啶-6-甲腈 | 1357470-29-1

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 8-环戊基-7,8-二氢-2-[[4-(4-甲基-1-哌嗪基)苯基]氨基]-7-氧代-吡啶并[2,3-d]嘧啶-6-甲腈
• 中文别名: 8-环戊基-7,8-二氢-2-[[4-(4-甲基-1-哌嗪基)苯基]氨基]-7-氧代-吡啶并[2,3-D]嘧啶-6-甲腈
• 英文名称: 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
• 英文别名: ON123300；8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile；8-cyclopentyl-2-[4-(4-methylpiperazin-1-yl)anilino]-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile
• CAS: 1357470-29-1
• 化学式: C₂₄H₂₇N₇O
• 分子量: 429.525
• InChiKey: VADOZMZXXRBXNY-UHFFFAOYSA-N

物化性质

• 沸点：
  642.7±65.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)
• 溶解度：
  ≥21.5 mg/mL，溶于 DMSO，温和加热；不溶于乙醇；不溶于水

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  88.4
• 氢给体数：
  1
• 氢受体数：
  7

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

用途

8-环戊基-7,8-二氢-2-[[4-(4-甲基-1-哌嗪基)苯基]氨基]-7-氧代-吡啶并[2,3-D]嘧啶-6-甲腈可用作多靶点激酶抑制剂和中间体，适用于科学研发与实验室研究。

生物活性

ON123300是有效的多靶点激酶抑制剂，其对CDK4、Ark5/NUAK1、PDGFRβ、FGFR1、RET (c-RET) 和 Fyn 的IC50值分别为3.9 nM、5 nM、26 nM、26 nM、9.2 nM和11 nM。

靶点

Target	Value
CDK4/CyclinD1 (Cell-free assay)	3.87 nM
ARK5 (Cell-free assay)	4.95 nM
RET (Cell-free assay)	9.2 nM
CDK6/CyclinD1 (Cell-free assay)	9.82 nM
Fyn (Cell-free assay)	11 nM

体外研究

ON123300抑制U87胶质瘤细胞的增殖，IC50为3.4±0.1 μmol/L；通过浓度依赖性和时间依赖性方式减少Akt的磷酸化并诱导Erk激活。这归因于ON123300减少了Akt介导的C-Raf S259位点失活，并通过PI3K负反馈调节激活p70S6K。该化合物还能抑制CDK4/6和PI3K-δ，对套细胞淋巴瘤（MCLs）具有有效的抑制活性。作为CDK4的有效抑制剂，IC50为3.8 nM；而对CDK1,2,5,8的活性甚微。

低浓度ON123300(0.1-1.0μM)处理的MCL细胞系在细胞周期G1期积累，高浓度处理下大部分细胞通过S和G2/M期，并最终积聚于sub-G1期。这表明诱导了细胞凋亡。此外，ON123300浓度依赖性地抑制pRB和p130的磷酸化；其处理将导致FOXO1磷酸化的抑制，而FOXO1是mTOR的靶标。

体内研究

在临床前脑肿瘤模型（U87MG）中，ON123300在脑部及脑肿瘤中大量积累。单药给药引起Akt浓度依赖式的抑制并在脑肿瘤中激活Erk。该化合物与血浆蛋白高度结合（99.4%），快速进入脑部，并具有良好的血脑屏障穿透能力，在正常脑部积累了较高的量。其药代动力学显示血药浓度呈多指数关系并迅速下降，终末消除半衰期为1.5小时。

小鼠异种移植瘤实验显示，在ON123300处理的动物中MCL肿瘤生长被显著抑制。在小鼠的安全性研究中，ON123300是一种具有口服生物活性的药物；通过口服或腹腔注射给药时，毒性作用非常小。

反应信息

• 作为反应物：
  描述：

  8-环戊基-7,8-二氢-2-[[4-(4-甲基-1-哌嗪基)苯基]氨基]-7-氧代-吡啶并[2,3-d]嘧啶-6-甲腈 、 4-三氟甲基苯甲酰氯 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.17h， 以62%的产率得到N-(6-cyano-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)-N-[4-(4-methyl-piperazin-1-yl)phenyl]-4-trifluoromethylbenzamide
  参考文献：
  名称：

  Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)

  摘要：

  The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2[-4-(4-methyl-piperazin-l-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARKS kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.

  DOI：

  10.1021/jm401073p
• 作为产物：
  描述：

  4-氨基-2-甲巯基嘧啶-5-甲醛 在 sodium hydride 、 溶剂黄146 、 间氯过氧苯甲酸 、 苄胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 11.08h， 生成 8-环戊基-7,8-二氢-2-[[4-(4-甲基-1-哌嗪基)苯基]氨基]-7-氧代-吡啶并[2,3-d]嘧啶-6-甲腈
  参考文献：
  名称：

  Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)

  摘要：

  The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2[-4-(4-methyl-piperazin-l-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARKS kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.

  DOI：

  10.1021/jm401073p

文献信息

• Quinolone-based compounds, formulations, and uses thereof
  申请人：Manetsch Roman

  公开号：US10000452B1

  公开（公告）日：2018-06-19

  Provided herein are quinolone-based compounds that can be used for treatment and/or prevention of malaria and formulations thereof. Also provided herein are methods of treating and/or preventing malaria in a subject by administering a quinolone-based compound or formulation thereof provided herein.

  本文提供了基于喹诺酮的化合物，可用于治疗和/或预防疟疾及其配方。本文还提供了通过给予本文提供的基于喹诺酮的化合物或配方来治疗和/或预防受试者疟疾的方法。
• [EN] CYCLIN-DEPENDENT KINASE INHIBITORS<br/>[FR] INHIBITEURS DE KINASES DÉPENDANTES DES CYCLINES
  申请人：SPV THERAPEUTICS INC

  公开号：WO2020140053A1

  公开（公告）日：2020-07-02

  Described herein are compounds and their pharmaceutically acceptable salts, pharmaceutical compositions thereof, methods of treatment, and medical uses. The compounds described herein are modulators of cyclin-dependent kinases, and are useful in the treatment or alleviation of protein kinase associated disorders, including cancer, infectious diseases, autoimmune diseases, or cardiovascular diseases.

  本文描述了化合物及其药用可接受的盐、药物组合物、治疗方法和医疗用途。本文描述的化合物是细胞周期依赖性激酶的调节剂，可用于治疗或缓解与蛋白激酶相关的疾病，包括癌症、传染病、自身免疫疾病或心血管疾病。
• [EN] 2-SUBSTITUTED-8-ALKYL-7-OXO-7,8-DIHYDROPYRIDO[2,3-D] PYRIMIDINE-6-CARBONITRILES AND USES THEREOF<br/>[FR] 8-ALKYL-7-OXO-7, 8DIHYDROPYRIDO[2,3-D] PYRIMIDINE-6-CARBONITRILES SUBSTITUÉS EN 2 ET LEURS UTILISATIONS
  申请人：UNIV TEMPLE

  公开号：WO2012018540A1

  公开（公告）日：2012-02-09

  Compounds according to Formula (I), as well as salts thereof: wherein R1 and R2 are as defined herein, are useful as antiproliferative agents and kinase inhibitors. Synthetic methods for preparing the compounds of Formula (I) are also provided.

  根据式（I）的化合物及其盐：其中R1和R2如本文所定义，可用作抗增殖剂和激酶抑制剂。还提供了制备式（I）化合物的合成方法。
• 2-SUBSTITUTED-8-ALKYL-7-OXO-7,8-DIHYDROPYRIDO[2,3-D] PYRIMIDINE-6-CARBONITRILES AND USES THEREOF
  申请人：Reddy E. Premkumar

  公开号：US20130131058A1

  公开（公告）日：2013-05-23

  Compounds according to Formula (I), as well salts thereof: wherein R 1 and R 2 are as defined herein, are useful as antiproliferative agents and kinase inhibitors. Synthetic methods for preparing the compounds of Formula (I) are also provided.

  根据化学式（I）及其盐，其中R1和R2的定义如下，这些化合物可用作抗增殖剂和激酶抑制剂。本发明还提供了制备化学式（I）化合物的合成方法。
• 2-SUBSTITUTED-8-ALKYL-7-OXO-7,8-DIHYDROPYRIDO[2,3-D]PYRIMIDINE-6-CARBONITRILES AND USES THEREOF
  申请人：Temple University - Of The Commonwealth System of Higher Education

  公开号：EP2600719B1

  公开（公告）日：2014-10-08