3-(5-cyano-6-(methyl(neopentyl)amino)-2-(methylsulfonyl)pyrimidin-4-ylamino)-N-methoxy-4-methylbenzamide | 868272-24-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-(5-cyano-6-(methyl(neopentyl)amino)-2-(methylsulfonyl)pyrimidin-4-ylamino)-N-methoxy-4-methylbenzamide
• 英文别名: 3-[[5-cyano-6-[2,2-dimethylpropyl(methyl)amino]-2-methylsulfonylpyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide
• CAS: 868272-24-6
• 化学式: C₂₁H₂₈N₆O₄S
• 分子量: 460.557
• InChiKey: ZDYZVGHPQVYUSJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  146
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  3-(5-cyano-6-(methyl(neopentyl)amino)-2-(methylsulfonyl)pyrimidin-4-ylamino)-N-methoxy-4-methylbenzamide 在 氨 作用下， 以 异丙醇 为溶剂， 反应 0.5h， 以29.5 mg的产率得到3-({2-amino-5-cyano-6-[(2,2-dimethylpropyl)(methyl)amino]pyrimidin-4-yl}amino)-N-methoxy-4-methylbenzamide
  参考文献：
  名称：

  5-Cyanopyrimidine Derivatives as a Novel Class of Potent, Selective, and Orally Active Inhibitors of p38α MAP Kinase

  摘要：

  A novel class of 5-cyanopyrimidine-based inhibitors of p38 alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (> 50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38 alpha.

  DOI：

  10.1021/jm0503594
• 作为产物：
  描述：

  4,6-二氯-5-氰基-2-甲硫基嘧啶 在 Oxone 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 38.0h， 生成 3-(5-cyano-6-(methyl(neopentyl)amino)-2-(methylsulfonyl)pyrimidin-4-ylamino)-N-methoxy-4-methylbenzamide
  参考文献：
  名称：

  5-Cyanopyrimidine Derivatives as a Novel Class of Potent, Selective, and Orally Active Inhibitors of p38α MAP Kinase

  摘要：

  A novel class of 5-cyanopyrimidine-based inhibitors of p38 alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (> 50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38 alpha.

  DOI：

  10.1021/jm0503594

文献信息

• 5-Cyanopyrimidine Derivatives as a Novel Class of Potent, Selective, and Orally Active Inhibitors of p38α MAP Kinase
  作者：Chunjian Liu、Stephen T. Wrobleski、James Lin、Gulzar Ahmed、Axel Metzger、John Wityak、Kathleen M. Gillooly、David J. Shuster、Kim W. McIntyre、Sidney Pitt、Ding Ren Shen、Rosemary F. Zhang、Hongjian Zhang、Arthur M. Doweyko、David Diller、Ian Henderson、Joel C. Barrish、John H. Dodd、Gary L. Schieven、Katerina Leftheris

  DOI：10.1021/jm0503594

  日期：2005.10.1

  A novel class of 5-cyanopyrimidine-based inhibitors of p38 alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (> 50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38 alpha.