(9R,12S)-12,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1{2,5}.0{4,9}.0{18,22}]tetracosa-1(21),2(24),4,15,17,19,22-heptaen-6-one | 1552314-49-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: (9R,12S)-12,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1{2,5}.0{4,9}.0{18,22}]tetracosa-1(21),2(24),4,15,17,19,22-heptaen-6-one
• 英文别名: (9R,12S)-12,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1~2,5~0~4,9~0~18,22~]tetracosa-1(21),2(24),4,15,17,19,22-heptaen-6-one；(9R,12S)-12,16-dimethyl-3,7,14,17,23-pentazapentacyclo[13.6.2.12,5.04,9.018,22]tetracosa-1(22),2(24),4,15(23),16,18,20-heptaen-6-one
• CAS: 1552314-49-4
• 化学式: C₂₁H₂₃N₅O
• 分子量: 361.447
• InChiKey: TUMIEGHWQWSXPG-WCQYABFASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  27
• 可旋转键数：
  0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  82.7
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (S)-2-甲基-1,4-丁二醇 在 溴 、 三苯基膦 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 49.0h， 生成 (9R,12S)-12,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1{2,5}.0{4,9}.0{18,22}]tetracosa-1(21),2(24),4,15,17,19,22-heptaen-6-one
  参考文献：
  名称：

  Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors

  摘要：

  The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests' that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxalinedihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macro cycles. The structure activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.

  DOI：

  10.1021/acsmedchemlett.5b00403

文献信息

• [EN] MACROCYCLES AS PIM INHIBITORS<br/>[FR] MACROCYCLES EN TANT QU'INHIBITEURS DE PIM
  申请人：AMGEN INC

  公开号：WO2014022752A1

  公开（公告）日：2014-02-06

  The invention relates to compounds of formula (1), and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.

  该发明涉及式（1）的化合物及其盐。在某些实施例中，该发明涉及Pim-1和/或Pim-2以及/或Pim-3蛋白激酶活性或酶功能的抑制剂或调节剂。在更进一步的实施例中，该发明涉及包含本文所披露的化合物的药物组合物，以及它们在预防和治疗与Pim激酶相关的疾病和病症，尤其是癌症中的用途。
• Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors
  作者：Victor J. Cee、Frank Chavez、Bradley Herberich、Brian A. Lanman、Liping H. Pettus、Anthony B. Reed、Bin Wu、Ryan P. Wurz、Kristin L. Andrews、Jie Chen、Dean Hickman、Jimmy Laszlo、Matthew R. Lee、Nadia Guerrero、Bethany K. Mattson、Yen Nguyen、Christopher Mohr、Karen Rex、Christine E. Sastri、Paul Wang、Qiong Wu、Tian Wu、Yang Xu、Yihong Zhou、Jeffrey T. Winston、J. Russell Lipford、Andrew S. Tasker、Hui-Ling Wang

  DOI：10.1021/acsmedchemlett.5b00403

  日期：2016.4.14

  The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests' that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxalinedihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macro cycles. The structure activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.