(5S,7R)-5-(3-bromo-5-fluorophenyl)-7-(3-bromophenyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine | 1609946-16-8

• 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: (5S,7R)-5-(3-bromo-5-fluorophenyl)-7-(3-bromophenyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine
• CAS: 1609946-16-8
• 化学式: C₁₆H₁₂Br₂FN₅
• 分子量: 453.111
• InChiKey: KYKKWYKMGWBEJU-LSDHHAIUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  55.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-溴-5-氟苯甲酸甲酯 在 sodium tetrahydroborate 、 sodium hydride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.75h， 生成 (5S,7R)-5-(3-bromo-5-fluorophenyl)-7-(3-bromophenyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine
  参考文献：
  名称：

  Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2

  摘要：

  Hypoxia inducible factor (HIF) transcription factors reside at the center of signaling pathways used by mammalian cells to sense and respond to low oxygen levels. While essential to maintain oxygen homeostasis, misregulation of HIF protein activity correlates with tumor development and metastasis. To provide artificial routes to target misregulated HIF activity, we identified small molecule antagonists of the HIF-2 transcription factor that bind an internal cavity within the C-terminal PAS domain of the HIF-2 alpha subunit. Here we describe a new class of chiral small molecule ligands that provide the highest affinity binding, the most effective, isoform-selective inhibition of HIP-2 in cells, and trigger the largest protein conformation changes reported to date. The current results further illuminate the molecular mechanism of HIF-2 antagonism and suggest additional routes to develop higher affinity and potency HIF-2 antagonists.

  DOI：

  10.1021/acs.jmedchem.5b00529

文献信息

• INHIBITION OF HIF-2ALPHA HETERODIMERIZATION WITH HIF1BETA (ARNT)
  申请人：THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

  公开号：US20160250216A1

  公开（公告）日：2016-09-01

  Provided is a method of inhibiting heterodimerization of HIF-2α to HIF1β (ARNT) comprising binding certain small molecules to the HIF-2α PAS-B domain cavity but not to HIF1α and inhibiting HIF-2α heterodimerization to HIF1β (ARNT) but not inhibiting HIF1α heterodimerization to HIF1β (ARNT). Those certain small molecules are also referenced synonymously as HIF2-HDI and HIF2α heterodimerization inhibitors and also simply as certain small molecules.

  提供了一种抑制HIF-2α与HIF1β（ARNT）异源二聚化的方法，包括将某些小分子结合到HIF-2α PAS-B结构域的空腔中，但不结合到HIF1α，从而抑制HIF-2α与HIF1β（ARNT）的异源二聚化，但不抑制HIF1α与HIF1β（ARNT）的异源二聚化。这些特定的小分子也被同义地称为HIF2-HDI和HIF2α异源二聚化抑制剂，也被简称为某些小分子。
• [EN] INHIBITION OF HIF-2α HETERODIMERIZATION WITH HIF1&bgr; (ARNT)<br/>[FR] INHIBITION DE L'HÉTÉRODIMÉRISATION DE HIF-2&Agr; AVEC HIF1&Bgr; (ARNT)
  申请人：UNIV TEXAS

  公开号：WO2014078479A3

  公开（公告）日：2014-07-17
• US9757379B2
  申请人：——

  公开号：US9757379B2

  公开（公告）日：2017-09-12
• Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2
  作者：Thomas H. Scheuermann、Daniel Stroud、Christopher E. Sleet、Liela Bayeh、Cameron Shokri、Hanzhi Wang、Charles G. Caldwell、Jamie Longgood、John B. MacMillan、Richard K. Bruick、Kevin H. Gardner、Uttam K. Tambar

  DOI：10.1021/acs.jmedchem.5b00529

  日期：2015.8.13

  Hypoxia inducible factor (HIF) transcription factors reside at the center of signaling pathways used by mammalian cells to sense and respond to low oxygen levels. While essential to maintain oxygen homeostasis, misregulation of HIF protein activity correlates with tumor development and metastasis. To provide artificial routes to target misregulated HIF activity, we identified small molecule antagonists of the HIF-2 transcription factor that bind an internal cavity within the C-terminal PAS domain of the HIF-2 alpha subunit. Here we describe a new class of chiral small molecule ligands that provide the highest affinity binding, the most effective, isoform-selective inhibition of HIP-2 in cells, and trigger the largest protein conformation changes reported to date. The current results further illuminate the molecular mechanism of HIF-2 antagonism and suggest additional routes to develop higher affinity and potency HIF-2 antagonists.