(1-phenyl-1H-pyrazol-4-yl)-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (1-phenyl-1H-pyrazol-4-yl)-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone
• 英文别名: (1-phenyl-1H-pyrazol-4-yl)-(1,3,4,5-tetrahydro-2H-pyrido[4,3-b]-indol-2-yl)methanone；(1-Phenylpyrazol-4-yl)-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone
• 化学式: C₂₁H₁₈N₄O
• 分子量: 342.4
• InChiKey: AVJCFQZEYNAZKI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  53.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  1-苯基-1H-吡唑-4-甲酸 、 2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚 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 N,N-二甲基甲酰胺 为溶剂， 反应 16.5h， 以26%的产率得到(1-phenyl-1H-pyrazol-4-yl)-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone
  参考文献：
  名称：

  Identification, Structure–Activity Relationship, and Biological Characterization of 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indoles as a Novel Class of CFTR Potentiators

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.0c01050

文献信息

• COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF CYSTIC FIBROSIS
  申请人：Fondazione Istituto Italiano Di Tecnologia

  公开号：US20210292324A1

  公开（公告）日：2021-09-23

  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.
• 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.