2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide | 1256448-47-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide
• 英文别名: N-hydroxy-2-(6-{[(6-fluoroquinoilin-2-yl)methyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxamide；N-hydroxy 2-{6-[(6-fluoroquinolin-2-ylmethyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide；CHR-3996
• CAS: 1256448-47-1
• 化学式: C₂₀H₁₉FN₆O₂
• 分子量: 394.408
• InChiKey: QRGHOAATPOLDPF-VQFNDLOPSA-N

物化性质

• 密度：
  1.51±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  1.51
• 重原子数：
  29.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  103.27
• 氢给体数：
  3.0
• 氢受体数：
  7.0

安全信息

• 储存条件：
  存储条件：2-8°C，密封保存，置于干燥处。

制备方法与用途

生物活性

Nanatinostat (CHR-3996) 是一种有效的、具有口服活性且对 I 类组蛋白去乙酰化酶 (HDAC) 具有选择性的抑制剂，其 IC50 值为 8 nM。

靶点 IC50：8 nM（针对 HDAC）

反应信息

• 作为产物：
  描述：

  (1R,5S,6s)-tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate 在 盐酸 、 甲醇 、 水 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 36.18h， 生成 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide
  参考文献：
  名称：

  Discovery of 2-(6-{[(6-Fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a Class I Selective Orally Active Histone Deacetylase Inhibitor

  摘要：

  A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC50 values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.

  DOI：

  10.1021/jm101177s

文献信息

• Methods of treating virally associated cancers with histone deacetylase inhibitors
  申请人：Viracta Therapeutics Inc.

  公开号：US10953011B2

  公开（公告）日：2021-03-23

  Described herein are certain dosing schedules and amounts that effectively prevent and manage side effects associated with histone deacetylase inhibitor (HDACi) treatment. Optionally, these schedules and dosing regimens include treatment with an antiviral agent.

  本文描述的某些给药方案和剂量能有效预防和控制组蛋白去乙酰化酶抑制剂（HDACi）治疗的副作用。可以选择的是，这些计划和给药方案包括抗病毒药物治疗。
• METHODS OF TREATING VIRALLY ASSOCIATED CANCERS WITH HISTONE DEACETYLASE INHIBITORS
  申请人：Viracta Therapeutics Inc.

  公开号：US20200375990A1

  公开（公告）日：2020-12-03

  Described herein are certain dosing schedules and amounts that effectively prevent and manage side effects associated with histone deacetylase inhibitor (HDACi) treatment. Optionally, these schedules and dosing regimens include treatment with an antiviral agent.
• Discovery of 2-(6-{[(6-Fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-<i>N</i>-hydroxypyrimidine-5-carboxamide (CHR-3996), a Class I Selective Orally Active Histone Deacetylase Inhibitor
  作者：David Moffat、Sanjay Patel、Francesca Day、Andrew Belfield、Alastair Donald、Martin Rowlands、Judata Wibawa、Deborah Brotherton、Lindsay Stimson、Vanessa Clark、Jo Owen、Lindsay Bawden、Gary Box、Elisabeth Bone、Paul Mortenson、Anthea Hardcastle、Sandra van Meurs、Suzanne Eccles、Florence Raynaud、Wynne Aherne

  DOI：10.1021/jm101177s

  日期：2010.12.23

  A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC50 values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.