(trans) 4-{[(3-iodo-7-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)methyl]amino}cyclohexanol | 760993-23-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (trans) 4-{[(3-iodo-7-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)methyl]amino}cyclohexanol
• CAS: 760993-23-5
• 化学式: C₁₈H₂₂IN₃O₂
• 分子量: 439.296
• InChiKey: FOKXHFMSFRYLPH-JOCQHMNTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.99
• 重原子数：
  24.0
• 可旋转键数：
  4.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  70.17
• 氢给体数：
  3.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (trans) 4-{[(3-iodo-7-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)methyl]amino}cyclohexanol 、 4-氰基苯硼酸 在 bis-triphenylphosphine-palladium(II) chloride sodium carbonate 作用下， 以 乙二醇二甲醚 、 乙醇 为溶剂， 生成
  参考文献：
  名称：

  Discovery of 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles and 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2′-carbonitriles as potent checkpoint kinase 1 (Chk1) inhibitors

  摘要：

  An extensive structure-activity relationship study of the 3-position of a series of tricyclic pyrazole-based Chk1 inhibitors is described. As a result, 4'-,1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles (4) and 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)pyridine-2'-carbonitriles (29) emerged as new lead series. Compared with the original lead compound 2, these new leads fully retain the biological activity in both enzymatic inhibition and cell-based assays. More importantly, the new leads 4 and 29 exhibit favorable physicochemical properties such as lower molecular weight, lower Clog P, and the absence of a hydroxyl group. Furthermore, structure-activity relationship studies were performed at the 6- and 7-positions of 4, which led to the identification of ideal Chk1 inhibitors 49, 50, 51, and 55. These compounds not only potently inhibit Chk1 in an enzymatic assay but also significantly potentiate the cytotoxicity of DNA-damaging agents in cell-based assays while they show little single agent activity. A cell cycle analysis by FACS confirmed that these Chk1 inhibitors efficiently abrogate the G2/M and S checkpoints induced by DNA-damaging agent. The current work paved the way to the identification of several potent Chk1 inhibitors with good pharmacokinetics that are suitable for in vivo study with oral dosing. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.07.102
• 作为产物：
  描述：

  6-bromo-7-methoxy-1,4-dihydroindeno[1,2-c]pyrazole 在 sodium tetrahydroborate 、 N-碘代丁二酰亚胺 、 仲丁基锂 、 对甲苯磺酸 、 苯基锂 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 生成 (trans) 4-{[(3-iodo-7-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)methyl]amino}cyclohexanol
  参考文献：
  名称：

  1,4-Dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: Extended exploration on phenyl ring substitutions and preliminary ADME/PK studies

  摘要：

  A study on substitutions at the four open positions on the phenyl ring of the 1,4-dihydroindeno[1,2-c]pyrazoles as potent CHK-1 inhibitors is described. Bis-substitution at both the 6- and 7-positions led to inhibitors with IC50 values below 0.3 nM. The compound with the best overall activities (36) was able to potentiate the anti-proliferative effect of doxorubicin in HeLa cells by at least 47-fold. Physicochemical, metabolic, and pharmacokinetic properties of selected inhibitors are also disclosed. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.04.055

文献信息

• [EN] FUSED TRI AND TETRA-CYCLIC PYRAZOLE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE PYRAZOLE KINASE FUSIONNEE TRICYCLIQUE ET TETRACYCLIQUE
  申请人：ABBOTT LAB

  公开号：WO2004080973A1

  公开（公告）日：2004-09-23

  Compounds having the formula (I) (I), are useful for inhibiting protein kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

  具有化学式(I) (I)的化合物对抑制蛋白激酶很有用。还公开了制备这些化合物的方法、含有这些化合物的组合物，以及使用这些化合物进行治疗的方法。