3-methyl-3H-benzo[e]indole-2-carboxylic acid | 221312-95-4

• 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: 3-methyl-3H-benzo[e]indole-2-carboxylic acid
• 英文别名: 3-methyl-3H-benz[e]indole-2-carboxylic acid；3-Methylbenzo[e]indole-2-carboxylic acid
• CAS: 221312-95-4
• 化学式: C₁₄H₁₁NO₂
• 分子量: 225.247
• InChiKey: OEUFSDRBSHPRNI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  42.2
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-[(1R)-1-氨基乙基]苯甲酸甲酯 、 3-methyl-3H-benzo[e]indole-2-carboxylic acid 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二甲基亚砜 为溶剂， 反应 1.58h， 生成
  参考文献：
  名称：

  Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis

  摘要：

  Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD(+))-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD(+).

  DOI：

  10.1021/acs.jmedchem.9b00718
• 作为产物：
  描述：

  methyl 3H-benz[e]indole-2-carboxylate 在 水 、 potassium carbonate 、 sodium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 3-methyl-3H-benzo[e]indole-2-carboxylic acid
  参考文献：
  名称：

  Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis

  摘要：

  Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD(+))-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD(+).

  DOI：

  10.1021/acs.jmedchem.9b00718

文献信息

• Indolecarboxylic compounds and their use as pharmaceutical compounds
  申请人：Societe L'Oreal S.A.

  公开号：US06448285B1

  公开（公告）日：2002-09-10

  The invention relates to the use, as active principle, in a physiologically acceptable medium, in a composition, of an effective amount of at least one compound of the indolecarboxylic family, this compound or these compositions being intended to treat disorders associated with overactivity of 5&agr;-reductase. These compounds or the compositions containing them are more particularly intended to treat androgen-dependent disorders such as seborrhoea and/or acne and/or hirsutism and/or androgenic alopecia. The invention also relates to novel compounds of the indolecarboxylic family and to compositions containing them.

  本发明涉及在生理可接受的介质中，在一种组合物中，作为活性成分使用，至少一种吲哚羧酸类化合物的有效量，该化合物或这些组合物用于治疗与5α-还原酶过度活性相关的紊乱。这些化合物或含有它们的组合物更特别地用于治疗雄激素依赖性紊乱，如皮脂溢和/或痤疮和/或多毛症和/或雄激素性脱发。本发明还涉及吲哚羧酸类的新化合物以及含有它们的组合物。
• Novel compounds of the indolecarboxylic family and use thereof
  申请人：——

  公开号：US20030050325A1

  公开（公告）日：2003-03-13

  The invention relates to the use, as active principle, in a physiologically acceptable medium, in a composition, of an effective amount of at least one compound of the indolecarboxylic family, this compound or these compositions being intended to treat disorders associated with overactivity of 5&agr;-reductase. These compounds or the compositions containing them are more particularly intended to treat androgen-dependent disorders such as, for example, seborrhoea and/or acne and/or hirsutism and/or androgenic alopecia. The invention also relates to novel compounds of the indolecarboxylic family and to compositions-containing them.

  本发明涉及在生理可接受介质中使用吲哚羧酸家族中至少一种化合物作为活性成分，并在组成物中使用有效量的该化合物或这些组成物，用于治疗与5α-还原酶过度活跃相关的疾病。这些化合物或含有它们的组成物特别适用于治疗雄激素依赖性疾病，例如皮脂溢出、痤疮、多毛症和雄激素性脱发。本发明还涉及吲哚羧酸家族的新化合物及含有它们的组成物。
• COMPOSES INDOLE-CARBOXYLIQUES ET LEUR UTILISATION COMME COMPOSES PHARMACEUTIQUES
  申请人：L'OREAL

  公开号：EP0964852B1

  公开（公告）日：2003-03-12
• US6448285B1
  申请人：——

  公开号：US6448285B1

  公开（公告）日：2002-09-10
• US6596753B2
  申请人：——

  公开号：US6596753B2

  公开（公告）日：2003-07-22