α,α-dimethyl-5H-[1]benzopyrano[2,3-b]pyridin-5-acetic acid | 1008119-13-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: α,α-dimethyl-5H-[1]benzopyrano[2,3-b]pyridin-5-acetic acid
• 英文别名: 2-(5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanoic acid
• CAS: 1008119-13-8
• 化学式: C₁₆H₁₅NO₃
• 分子量: 269.3
• InChiKey: LTGFBILAUODUPP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  59.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-氨基-1,3,4-噻二唑 、 α,α-dimethyl-5H-[1]benzopyrano[2,3-b]pyridin-5-acetic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 以150 mg的产率得到α,α-dimethyl-N-(1,3,4-thiadiazol-2-yl)-5H-[1]benzopyrano[2,3-b]pyridin-5-acetamide
  参考文献：
  名称：

  Azaxanthene Based Selective Glucocorticoid Receptor Modulators: Design, Synthesis, and Pharmacological Evaluation of (S)-4-(5-(1-((1,3,4-Thiadiazol-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-5H-chromeno[2,3-b]pyridin-2-yl)-2-fluoro-N,N-dimethylbenzamide (BMS-776532) and Its Methylene Homologue (BMS-791826)

  摘要：

  Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of dose structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.

  DOI：

  10.1021/jm200879j
• 作为产物：
  描述：

  5H-[1]-苯并吡喃o[2,3-b]吡啶-5-醇 在 四氯化钛 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 11.17h， 生成 α,α-dimethyl-5H-[1]benzopyrano[2,3-b]pyridin-5-acetic acid
  参考文献：
  名称：

  Azaxanthene Based Selective Glucocorticoid Receptor Modulators: Design, Synthesis, and Pharmacological Evaluation of (S)-4-(5-(1-((1,3,4-Thiadiazol-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-5H-chromeno[2,3-b]pyridin-2-yl)-2-fluoro-N,N-dimethylbenzamide (BMS-776532) and Its Methylene Homologue (BMS-791826)

  摘要：

  Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of dose structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.

  DOI：

  10.1021/jm200879j

文献信息

• Azaxanthene Based Selective Glucocorticoid Receptor Modulators: Design, Synthesis, and Pharmacological Evaluation of (<i>S</i>)-4-(5-(1-((1,3,4-Thiadiazol-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-5<i>H</i>-chromeno[2,3-<i>b</i>]pyridin-2-yl)-2-fluoro-<i>N</i>,<i>N</i>-dimethylbenzamide (BMS-776532) and Its Methylene Homologue (BMS-791826)
  作者：David S. Weinstein、Hua Gong、Arthur M. Doweyko、Mark Cunningham、Sium Habte、Jin Hong Wang、Deborah A. Holloway、Christine Burke、Ling Gao、Victor Guarino、Julie Carman、John E. Somerville、David Shuster、Luisa Salter-Cid、John H. Dodd、Steven G. Nadler、Joel C. Barrish

  DOI：10.1021/jm200879j

  日期：2011.10.27

  Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of dose structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.