N-(6-(4-(dimethylamino)piperidin-1-yl)pyridazin-3-yl)-9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine | 1588958-90-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: N-(6-(4-(dimethylamino)piperidin-1-yl)pyridazin-3-yl)-9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine
• 英文别名: N-(6-(4-(dimethylamino)-1-piperidinyl)-3-pyridazinyl)-9-(trans-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine
• CAS: 1588958-90-0
• 化学式: C₂₇H₃₅N₉
• 分子量: 485.635
• InChiKey: AXXUSLKWELMYSS-KESTWPANSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.79
• 重原子数：
  36.0
• 可旋转键数：
  5.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  87.89
• 氢给体数：
  1.0
• 氢受体数：
  9.0

反应信息

• 作为产物：
  描述：

  在 bis-triphenylphosphine-palladium(II) chloride 、 tris-(dibenzylideneacetone)dipalladium(0) 、 sodium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 sodium t-butanolate 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.0h， 生成 N-(6-(4-(dimethylamino)piperidin-1-yl)pyridazin-3-yl)-9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine
  参考文献：
  名称：

  Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3

  摘要：

  We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb+) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

  DOI：

  10.1021/jm500118j

文献信息

• METHODS OF USING CELL-CYCLE INHIBITORS TO MODULATE ONE OR MORE PROPERTIES OF A CELL CULTURE
  申请人：AMGEN INC.

  公开号：US20150353542A1

  公开（公告）日：2015-12-10

  Methods of modulating the properties of a cell culture expressing a protein of interest are provided. In various embodiments the methods relate to the addition of cell cycle inhibitors to growing cell cultures.

  提供了一种调节表达感兴趣蛋白的细胞培养物性质的方法。在各种实施方式中，该方法涉及向生长的细胞培养物中添加细胞周期抑制剂。
• [EN] METHODS OF USING CELL-CYCLE INHIBITORS TO MODULATE ONE OR MORE PROPERTIES OF A CELL CULTURE<br/>[FR] MÉTHODES D'UTILISATION D'INHIBITEURS DE CYCLE CELLULAIRE POUR MODULER UNE OU PLUSIEURS PROPRIÉTÉS D'UNE CULTURE CELLULAIRE
  申请人：AMGEN INC

  公开号：WO2014109858A1

  公开（公告）日：2014-07-17

  Methods of modulating the properties of a cell culture expressing a protein of interest are provided. In various embodiments the methods relate to the addition of cell cycle inhibitors to growing cell cultures.
• Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3
  作者：Zhihong Li、Xianghong Wang、John Eksterowicz、Michael W. Gribble、Grace Q. Alba、Merrill Ayres、Timothy J. Carlson、Ada Chen、Xiaoqi Chen、Robert Cho、Richard V. Connors、Michael DeGraffenreid、Jeffrey T. Deignan、Jason Duquette、Pingchen Fan、Benjamin Fisher、Jiasheng Fu、Justin N. Huard、Jacob Kaizerman、Kathleen S. Keegan、Cong Li、Kexue Li、Yunxiao Li、Lingming Liang、Wen Liu、Sarah E. Lively、Mei-Chu Lo、Ji Ma、Dustin L. McMinn、Jeffrey T. Mihalic、Kriti Modi、Rachel Ngo、Kanaka Pattabiraman、Derek E. Piper、Christophe Queva、Mark L. Ragains、Julia Suchomel、Steve Thibault、Nigel Walker、Xiaodong Wang、Zhulun Wang、Malgorzata Wanska、Paul M. Wehn、Margaret F. Weidner、Alex J. Zhang、Xiaoning Zhao、Alexander Kamb、Dineli Wickramasinghe、Kang Dai、Lawrence R. McGee、Julio C. Medina

  DOI：10.1021/jm500118j

  日期：2014.4.24

  We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb+) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.