4-methyl-N-[2-[[4-(3-piperidyloxy)phenoxy]methyl]phenyl]-thieno[3,2-b]pyrrole-5-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-methyl-N-[2-[[4-(3-piperidyloxy)phenoxy]methyl]phenyl]-thieno[3,2-b]pyrrole-5-carboxamide
• 英文别名: 4-methyl-N-[2-[(4-piperidin-3-yloxyphenoxy)methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide
• 化学式: C₂₆H₂₇N₃O₃S
• 分子量: 461.585
• InChiKey: BAJBBYYUVNGYKO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  92.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4H-噻吩[3,2-b]吡咯-5-羧酸乙酯 在 盐酸 、 氯化亚砜 、 偶氮二甲酸二异丙酯 、 水 、 sodium hydride 、 N,N-二甲基甲酰胺 、 三苯基膦 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 6.17h， 生成 4-methyl-N-[2-[[4-(3-piperidyloxy)phenoxy]methyl]phenyl]-thieno[3,2-b]pyrrole-5-carboxamide
  参考文献：
  名称：

  Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure–Activity Relationship

  摘要：

  The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described (Part 1, DOI 10.1021.acs.jmedchem.6b01018) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and SO showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.

  DOI：

  10.1021/acs.jmedchem.6b01019

文献信息

• Thienopyrroles as histone demethylase inhibitors
  申请人：IEO - Istituto Europeo di Oncologia Srl

  公开号：EP2993175A1

  公开（公告）日：2016-03-09

  The present invention relates to thienopyrrole derivatives, wherein R, R1, R2 and R3 are as defined in the specification, pharmaceutical compositions containing such compounds and to their use in therapy.

  本发明涉及噻吩吡咯衍生物（其中 R、R1、R2 和 R3 如说明书中所定义）、含有此类化合物的药物组合物及其在治疗中的用途。
• THIENOPYRROLES AS HISTONE DEMETHYLASE INHIBITORS
  申请人：Istituto Europeo di Oncologia S.r.l.

  公开号：EP3189059A2

  公开（公告）日：2017-07-12
• USE OF A COMBINATIONAL THERAPY OF LSD1 INHIBITORS WITH CDK2 INHIBITORS IN THE TREATMENT OF CANCER
  申请人：Rasna Therapeutics Limited

  公开号：US20180311245A1

  公开（公告）日：2018-11-01

  The present disclosure relates to methods of treating cancer and pharmaceutical compositions for use in the treatment of cancer, including LSD1-inhibitor-resistant cancers, comprising administering to a subject an effective amount of a CDK2 inhibitor and an effective amount of a LSD1 inhibitor.
• USE OF A COMBINATIONAL THERAPY OF LSD1 INHIBITORS WITH P21 ACTIVATORS IN THE TREATMENT OF CANCER
  申请人：Istituto Europeo di Oncologia S.r.l.

  公开号：US20210100800A1

  公开（公告）日：2021-04-08

  The present disclosure relates to methods of treating cancer and pharmaceutical compositions for use in the treatment of cancer, including LSD1-inhibitor-resistant cancers, comprising administering to a subject an effective amount of a cell cycle inhibitor, such as a CDK4/6 inhibitor or a p21 enhancer, and an effective amount of a LSD1 inhibitor.
• [EN] THIENOPYRROLES AS HISTONE DEMETHYLASE INHIBITORS<br/>[FR] THIÉNOPYRROLES COMME INHIBITEURS DE L'HISTONE DÉMÉTHYLASE
  申请人：ISTITUTO EUROP DI ONCOLOGIA S R L

  公开号：WO2016034946A2

  公开（公告）日：2016-03-10

  The present application relates to thienopyrrole derivatives, compounds of Formulae (I) and (la), wherein R, R1, R2 and R3 are as defined in the specification, pharmaceutical compositions containing such compounds and to their use in therapy. The compounds of the application can be useful for inhibiting KDM1 and the prevention and/or treatment of cancer, infectious disease, or a disease characterized by aberration of cellular energy metabolism, e.g., obesity.