4-(3-cyclopropyl-1H-pyrazol-4-yl)-2-methanesulfonyl-pyrimidine | 1256963-12-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-(3-cyclopropyl-1H-pyrazol-4-yl)-2-methanesulfonyl-pyrimidine
• CAS: 1256963-12-8
• 化学式: C₁₁H₁₂N₄O₂S
• 分子量: 264.308
• InChiKey: NCXCLWNNJZRLGE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.15
• 重原子数：
  18.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  88.6
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯 、 4-(3-cyclopropyl-1H-pyrazol-4-yl)-2-methanesulfonyl-pyrimidine 以 甲苯 为溶剂， 反应 16.0h， 生成
  参考文献：
  名称：

  4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6

  摘要：

  Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK 4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK 6. Significant selectivity for CDK4/6 over CDK 1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.

  DOI：

  10.1021/jm100571n
• 作为产物：
  描述：

  在 oxone 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 4-(3-cyclopropyl-1H-pyrazol-4-yl)-2-methanesulfonyl-pyrimidine
  参考文献：
  名称：

  4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6

  摘要：

  Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK 4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK 6. Significant selectivity for CDK4/6 over CDK 1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.

  DOI：

  10.1021/jm100571n

文献信息

• Lead Optimization toward Proof-of-Concept Tools for Huntington’s Disease within a 4-(1<i>H</i>-Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors
  作者：John Wityak、Kevin F. McGee、Michael P. Conlon、Ren Hua Song、Bryan C. Duffy、Brent Clayton、Michael Lynch、Gwen Wang、Emily Freeman、James Haber、Douglas B. Kitchen、David D. Manning、Jiffry Ismail、Yuri Khmelnitsky、Peter Michels、Jeff Webster、Macarena Irigoyen、Michele Luche、Monica Hultman、Mei Bai、IokTeng D. Kuok、Ryan Newell、Marieke Lamers、Philip Leonard、Dawn Yates、Kim Matthews、Lynette Ongeri、Steve Clifton、Tania Mead、Susan Deupree、Pat Wheelan、Kathy Lyons、Claire Wilson、Alex Kiselyov、Leticia Toledo-Sherman、Maria Beconi、Ignacio Muñoz-Sanjuan、Jonathan Bard、Celia Dominguez

  DOI：10.1021/jm5013598

  日期：2015.4.9

  Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.