2-fluoro-N-{2-[6-(morpholin-4-yl)pyridin-3-yl]propan-2-yl}-9-oxo-9,10-dihydroacridine-3-carboxamide

• 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-fluoro-N-{2-[6-(morpholin-4-yl)pyridin-3-yl]propan-2-yl}-9-oxo-9,10-dihydroacridine-3-carboxamide
• 英文别名: 2-fluoro-N-[2-(6-morpholin-4-ylpyridin-3-yl)propan-2-yl]-9-oxo-10H-acridine-3-carboxamide
• 化学式: C₂₆H₂₅FN₄O₃
• 分子量: 460.508
• InChiKey: JNULEICLWFEONX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  83.6
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  二氟-对苯二酸二甲酯 在 palladium on activated charcoal lithium hydroxide 、 PPA 、 N,N-bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride 、 硫酸 、 氢气 、 硝酸 、 palladium diacetate 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 25.92h， 生成 2-fluoro-N-{2-[6-(morpholin-4-yl)pyridin-3-yl]propan-2-yl}-9-oxo-9,10-dihydroacridine-3-carboxamide
  参考文献：
  名称：

  Acridone-Based Inhibitors of Inosine 5‘-Monophosphate Dehydrogenase:  Discovery and SAR Leading to the Identification of N-(2-(6-(4-Ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2- fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide (BMS-566419)

  摘要：

  Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.

  DOI：

  10.1021/jm070299x

文献信息

• Acridone-Based Inhibitors of Inosine 5‘-Monophosphate Dehydrogenase:  Discovery and SAR Leading to the Identification of <i>N</i>-(2-(6-(4-Ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2- fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide (BMS-566419)
  作者：Scott H. Watterson、Ping Chen、Yufen Zhao、Henry H. Gu、T. G. Murali Dhar、Zili Xiao、Shelley K. Ballentine、Zhongqi Shen、Catherine A. Fleener、Katherine A. Rouleau、Mary Obermeier、Zheng Yang、Kim W. McIntyre、David J. Shuster、Mark Witmer、Donna Dambach、Sam Chao、Arvind Mathur、Bang-Chi Chen、Joel C. Barrish、Jeffrey A. Robl、Robert Townsend、Edwin J. Iwanowicz

  DOI：10.1021/jm070299x

  日期：2007.7.1

  Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.