4-((2-fluoro-6-(trifluoromethyl)benzyl)amino)-2-((isoxazol-3-ylmethyl)amino)quinazoline-8-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 4-((2-fluoro-6-(trifluoromethyl)benzyl)amino)-2-((isoxazol-3-ylmethyl)amino)quinazoline-8-carboxamide
• 英文别名: 4-[[2-Fluoro-6-(trifluoromethyl)phenyl]methylamino]-2-(1,2-oxazol-3-ylmethylamino)quinazoline-8-carboxamide；4-[[2-fluoro-6-(trifluoromethyl)phenyl]methylamino]-2-(1,2-oxazol-3-ylmethylamino)quinazoline-8-carboxamide
• 化学式: C₂₁H₁₆F₄N₆O₂
• 分子量: 460.391
• InChiKey: VHMQDBQWAAHFOU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  119
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  2-氯-6-(三氟甲基)苄胺 在 双氧水 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二甲基亚砜 为溶剂， 反应 37.0h， 生成 4-((2-fluoro-6-(trifluoromethyl)benzyl)amino)-2-((isoxazol-3-ylmethyl)amino)quinazoline-8-carboxamide
  参考文献：
  名称：

  2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships

  摘要：

  Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10-100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models. (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2018.03.021

文献信息

• 2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships
  作者：David N. Deaton、Curt D. Haffner、Brad R. Henke、Michael R. Jeune、Barry G. Shearer、Eugene L. Stewart、J. Darren Stuart、John C. Ulrich

  DOI：10.1016/j.bmc.2018.03.021

  日期：2018.5

  Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10-100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models. (C) 2018 Elsevier Ltd. All rights reserved.