N-(3-(quinuclidin-3-yl)-1H-indol-6-yl)thiophene-2-carboximidamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N-(3-(quinuclidin-3-yl)-1H-indol-6-yl)thiophene-2-carboximidamide
• 英文别名: N'-[3-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1H-indol-6-yl]thiophene-2-carboximidamide
• 化学式: C₂₀H₂₂N₄S
• 分子量: 350.487
• InChiKey: OHHGHMJEPXHYDM-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  85.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3-(6-nitro-1H-indol-3-yl)-1-azabicyclo[2.2.2]oct-2-ene 在 二氧化碳 、 20% palladium hydroxide on charcoal 、 氢气 作用下， 以 乙醇 、 异丙醇 为溶剂， 20.0 ℃ 、10.0 MPa 条件下， 反应 96.0h， 生成 N-(3-(quinuclidin-3-yl)-1H-indol-6-yl)thiophene-2-carboximidamide 、 N-(3-(quinuclidin-3-yl)-1H-indol-6-yl)thiophene-2-carboximidamide
  参考文献：
  名称：

  Discovery of N-(3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-6-yl) thiophene-2-carboximidamide as a Selective Inhibitor of Human Neuronal Nitric Oxide Synthase (nNOS) for the Treatment of Pain

  摘要：

  3,6-Disubstituted indole derivatives were designed, synthesized, and evaluated as inhibitors of human nitric oxide synthase (NOS). Bulky amine containing substitution on the 3-position of the indole ring such as an azabicyclic system showed better selectivity over 5- and 6-membered cyclic amine substitutions. Compound (-)-19 showed the best selectivity for neuronal NOS over endothelial NOS (90-fold) and inducible NOS (309-fold) among the current series. Compounds 16 and (-)-19 were shown to be either inactive or very weak inhibitors of human cytochrome P450 enzymes, indicating a low potential for drug drug interactions. Compound 16 was shown to reverse thermal hyperalgesia in vivo in the Chung model of neuropathic pain. Compound 16 was also devoid of any significant vasoconstrictive effect in human coronary arteries, associated with the inhibition of human eNOS. These results suggest that 16 may be a useful tool for evaluating the potential role of selective nNOS inhibitors in the treatment of pain such as migraine and CTTH.

  DOI：

  10.1021/jm201063u

文献信息

• Discovery of <i>N</i>-(3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1<i>H</i>-indol-6-yl) thiophene-2-carboximidamide as a Selective Inhibitor of Human Neuronal Nitric Oxide Synthase (nNOS) for the Treatment of Pain
  作者：Subhash C. Annedi、Shawn P. Maddaford、Gabriela Mladenova、Jailall Ramnauth、Suman Rakhit、John S. Andrews、David K. H. Lee、Dongqin Zhang、Frank Porreca、David Bunton、Lee Christie

  DOI：10.1021/jm201063u

  日期：2011.10.27

  3,6-Disubstituted indole derivatives were designed, synthesized, and evaluated as inhibitors of human nitric oxide synthase (NOS). Bulky amine containing substitution on the 3-position of the indole ring such as an azabicyclic system showed better selectivity over 5- and 6-membered cyclic amine substitutions. Compound (-)-19 showed the best selectivity for neuronal NOS over endothelial NOS (90-fold) and inducible NOS (309-fold) among the current series. Compounds 16 and (-)-19 were shown to be either inactive or very weak inhibitors of human cytochrome P450 enzymes, indicating a low potential for drug drug interactions. Compound 16 was shown to reverse thermal hyperalgesia in vivo in the Chung model of neuropathic pain. Compound 16 was also devoid of any significant vasoconstrictive effect in human coronary arteries, associated with the inhibition of human eNOS. These results suggest that 16 may be a useful tool for evaluating the potential role of selective nNOS inhibitors in the treatment of pain such as migraine and CTTH.