2-((2-((R)-3-aminopiperidin-1-yl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-3-yl)methyl)benzonitrile | 1245810-97-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 2-((2-((R)-3-aminopiperidin-1-yl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-3-yl)methyl)benzonitrile
• 英文别名: 2-[[2-[(3R)-3-aminopiperidin-1-yl]-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]benzonitrile
• CAS: 1245810-97-2
• 化学式: C₁₉H₂₀N₆O
• 分子量: 348.407
• InChiKey: IKBHLSXOWMBCEJ-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-((2-((R)-3-aminopiperidin-1-yl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-3-yl)methyl)benzonitrile 在 N-溴代丁二酰亚胺(NBS) 、 四(三苯基膦)钯 、 potassium carbonate 、 叔丁胺 作用下， 以 二氯甲烷 、 水 、 异丙醇 为溶剂， 反应 4.5h， 生成 tert-butyl ((3R)-1-(3-(2-cyanobenzyl)-4-oxo-6-(4-(trifluoromethyl)phenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-3-yl)carbamate
  参考文献：
  名称：

  Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization

  摘要：

  We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.03.015
• 作为产物：
  描述：

  2,4-二氯-7H吡咯[2,3-D]嘧啶 在 4-二甲氨基吡啶 、 sodium hydride 、 碳酸氢钠 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.83h， 生成 2-((2-((R)-3-aminopiperidin-1-yl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-3-yl)methyl)benzonitrile
  参考文献：
  名称：

  Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization

  摘要：

  We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.03.015

文献信息

• Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization
  作者：Hui Xie、Lili Zeng、Shaogao Zeng、Xin Lu、Guicheng Zhang、Xin Zhao、Na Cheng、Zhengchao Tu、Zhiyuan Li、Hongjiang Xu、Ling Yang、Xiquan Zhang、Min Huang、Junling Zhao、Wenhui Hu

  DOI：10.1016/j.ejmech.2012.03.015

  日期：2012.6

  We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development. (C) 2012 Elsevier Masson SAS. All rights reserved.