5-(azetidin-1-ylcarbonyl)-3-methyl-6-{[2-(methylamino)-1H-1,3-benzodiazol-1-yl]methyl}-1-(2-methylpropyl)-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-2,4-dione | 1026097-40-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: 5-(azetidin-1-ylcarbonyl)-3-methyl-6-{[2-(methylamino)-1H-1,3-benzodiazol-1-yl]methyl}-1-(2-methylpropyl)-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-2,4-dione
• 英文别名: 5-(azetidine-1-carbonyl)-3-methyl-6-[[2-(methylamino)benzimidazol-1-yl]methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-dione
• CAS: 1026097-40-4
• 化学式: C₂₄H₂₈N₆O₃S
• 分子量: 480.591
• InChiKey: FVIJIRCHSMDMJH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  119
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  methyl 6-bromomethyl-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate 在 异丙基氯化镁 、 potassium carbonate 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.5h， 生成 5-(azetidin-1-ylcarbonyl)-3-methyl-6-{[2-(methylamino)-1H-1,3-benzodiazol-1-yl]methyl}-1-(2-methylpropyl)-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-2,4-dione
  参考文献：
  名称：

  Optimization of Monocarboxylate Transporter 1 Blockers through Analysis and Modulation of Atropisomer Interconversion Properties

  摘要：

  We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.

  DOI：

  10.1021/jm060995h

文献信息

• Optimization of Monocarboxylate Transporter 1 Blockers through Analysis and Modulation of Atropisomer Interconversion Properties
  作者：Simon D. Guile、John R. Bantick、Martin E. Cooper、David K. Donald、Christine Eyssade、Anthony H. Ingall、Richard J. Lewis、Barrie P. Martin、Rukhsana T. Mohammed、Timothy J. Potter、Rachel H. Reynolds、Stephen A. St-Gallay、Andrew D. Wright

  DOI：10.1021/jm060995h

  日期：2007.1.1

  We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.