8-methylsulfonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

• 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: 8-methylsulfonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
• 英文别名: 8-methanesulfonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole；8-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl
• 化学式: C₁₂H₁₄N₂O₂S
• 分子量: 250.321
• InChiKey: LJUQWGXQKULTCE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  70.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  8-methylsulfonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 、 反式-1,2-环己二羧酸酐 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (1R,2R)-N-(1-cyanocyclopropyl)-2-{[8-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]carbonyl}cyclohexanecarboxamide
  参考文献：
  名称：

  (1R,2R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A Potent and Highly Selective Cathepsin K Inhibitor for the Treatment of Osteoarthritis

  摘要：

  Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.

  DOI：

  10.1021/jm3007257
• 作为产物：
  描述：

  4-甲磺酰基苯肼盐酸盐 在 三氟化硼乙醚 、 溶剂黄146 作用下， 以 乙醇 、 水 为溶剂， 反应 3.0h， 生成 8-methylsulfonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
  参考文献：
  名称：

  (1R,2R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A Potent and Highly Selective Cathepsin K Inhibitor for the Treatment of Osteoarthritis

  摘要：

  Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.

  DOI：

  10.1021/jm3007257

文献信息

• Novel Compound - 827
  申请人：Dossetter Alexander Graham

  公开号：US20090012077A1

  公开（公告）日：2009-01-08

  The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases, including cathepsins B, K, C, F, H, L, O, S, W and X. Of particular interest are diseases associated with Cathepsin K.

  本发明涉及用于治疗与半胱氨酸蛋白酶活性相关疾病的化合物和组合物。这些化合物是半胱氨酸蛋白酶的可逆抑制剂，包括卡特普辛B、K、C、F、H、L、O、S、W和X。特别感兴趣的是与卡特普辛K相关的疾病。
• [EN] COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF CYSTIC FIBROSIS<br/>[FR] COMPOSÉS ET COMPOSITIONS POUR LE TRAITEMENT DE LA FIBROSE KYSTIQUE
  申请人：FONDAZIONE ST ITALIANO TECNOLOGIA

  公开号：WO2020012427A1

  公开（公告）日：2020-01-16

  The present invention relates to compounds of Formula (Ia) or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, stereoisomers thereof. It further discloses a pharmaceutical composition comprising the compounds of Formula (Ia) and the use of compounds of Formula (Ib), in particular to modulate CFTR protein or ABC protein activities.

  本发明涉及式(Ia)的化合物或其药学上可接受的盐、水合物、溶剂合物、包合物、多形体、立体异构体。进一步披露了一种包含式(Ia)的化合物的药物组合物，以及利用式(Ib)的化合物，特别是用于调节CFTR蛋白或ABC蛋白活性。
• Synthesis and biological activity of N-aroyl-tetrahydro-γ-carbolines
  作者：Alexandre Bridoux、Régis Millet、Jean Pommery、Nicole Pommery、Jean-Pierre Henichart

  DOI：10.1016/j.bmc.2010.04.034

  日期：2010.6.1

  Research on dual inhibitors of both 5-LOX and COXs gained interest due to the overexpressions of these enzymes during the malignant state of the evolution of prostate cancer. In order to take part in this research, new N-aroyl-tetrahydro-gamma-carbolines issued from the modi. cation of Indomethacin have been synthesised. As for the NSAIDs, the compounds have been tested for their activity against COX1, COX2 plus against 5-LOX and against the proliferation of malignant prostate cancer. Interesting cytotoxic activities and selectivities of some tetrahydro-gamma-carboline derivatives have been obtained. (C) 2010 Elsevier Ltd. All rights reserved.
• Identification, Structure–Activity Relationship, and Biological Characterization of 2,3,4,5-Tetrahydro-1<i>H</i>-pyrido[4,3-<i>b</i>]indoles as a Novel Class of CFTR Potentiators
  作者：Nicoletta Brindani、Ambra Gianotti、Simone Giovani、Francesca Giacomina、Paolo Di Fruscia、Federico Sorana、Sine Mandrup Bertozzi、Giuliana Ottonello、Luca Goldoni、Ilaria Penna、Debora Russo、Maria Summa、Rosalia Bertorelli、Loretta Ferrera、Emanuela Pesce、Elvira Sondo、Luis J. V. Galietta、Tiziano Bandiera、Nicoletta Pedemonte、Fabio Bertozzi

  DOI：10.1021/acs.jmedchem.0c01050

  日期：2020.10.8

  Cystic fibrosis (CF) is a life-threatening autosomal recessive disease, caused by mutations in the CF transmembrane conductance regulator (CFTR) chloride channel. CFTR modulators have been reported to address the basic defects associated with CF-causing mutations, partially restoring the CFTR function in terms of protein processing and/or channel gating. Small-molecule compounds, called potentiators, are known to ameliorate the gating defect. In this study, we describe the identification of the 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole core as a novel chemotype of potentiators. In-depth structure-activity relationship studies led to the discovery of enantiomerically pure 39 endowed with a good efficacy in rescuing the gating defect of F508del- and G551D-CFTR and a promising in vitro druglike profile. The in vivo characterization of gamma-carboline 39 showed considerable exposure levels and good oral bioavailability, with detectable distribution to the lungs after oral administration to rats. Overall, these findings may represent an encouraging starting point to further expand this chemical class, adding a new chemotype to the existing classes of CFTR potentiators.
• 1-CYANOCYCLOPROPYL-DERIVATIVES AS CATHEPSIN K INHIBITORS
  申请人：AstraZeneca AB

  公开号：EP2170879B1

  公开（公告）日：2013-01-16