3-benzyl-1-(but-2-yn-1-yl)-6-chloropyrimidine-2,4(1H,3H)-dione | 1431528-76-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 3-benzyl-1-(but-2-yn-1-yl)-6-chloropyrimidine-2,4(1H,3H)-dione
• 英文别名: 3-benzyl-1-(but-2-ynyl)-6-chloropyrimidine-2,4(1H,3H)-dione
• CAS: 1431528-76-5
• 化学式: C₁₅H₁₃ClN₂O₂
• 分子量: 288.733
• InChiKey: WVJDPZMOOKAEGJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.74
• 重原子数：
  20.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  44.0
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  3-benzyl-1-(but-2-yn-1-yl)-6-chloropyrimidine-2,4(1H,3H)-dione 在 盐酸 、 potassium carbonate 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 (R)-6-(3-aminopiperidin-1-yl)-3-benzyl-1-(but-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione hydrochloride
  参考文献：
  名称：

  尿嘧啶基苯甲酸及其酯衍生物作为治疗 2 型糖尿病的新型二肽基肽酶 4 抑制剂的鉴定及构效关系探索

  摘要：

  我们之前报道的含羧基的 DPP-4 抑制剂非常有效，但生物利用度很低。羧基类似物的酯表现出显着的 DPP-4 效力损失，尽管具有增强的口服吸收。在此，我们描述了一系列新型苯甲酸和酯衍生物作为低个位数纳摩尔 DPP-4 抑制剂的鉴定和构效关系 (SAR) 探索。重要的是，酯显示出与酸对应物相当的活性。分子模拟显示酯采用与酸相似的结合方式。此外，所选择的酯和酸表现出高选择性和低细胞毒性，以及良好的代谢稳定性。更重要的是，这些酯类具有出色的口服药代动力学特征。最好的复合酯图19b在体内证明了长时间的 DPP-4 抑制，并在正常和 db/db 小鼠中显着改善了葡萄糖耐量，同时确保了慢性治疗中的降糖效力。我们的结果支持化合物19b可作为治疗 2 型糖尿病的潜在候选药物。

  DOI：

  10.1016/j.ejmech.2021.113765
• 作为产物：
  描述：

  1-(but-2-ynyl)-6-chloropyrimidine-2,4(1H,3H)-dione 、 氯化苄 在 sodium hydride 、 lithium bromide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 以69%的产率得到3-benzyl-1-(but-2-yn-1-yl)-6-chloropyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin

  摘要：

  Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. The most promising compound 2h (IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that of alogliptin (IC50 = 2.63 nM) and linagliptin (IC50 = 0.77 nM), respectively. Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus was selected for further biological evaluation, including oral glucose tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute toxicity and hERG inhibition. The assay results showed that 2h displayed significant in vivo glucose-lowering effect and low risk of toxicity. Further studies are expected to confirm 2h as a potential drug candidate for the treatment of type 2 diabetes.

  DOI：

  10.1016/j.ejmech.2014.06.044

文献信息

• Highly potent dipeptidyl peptidase IV inhibitors derived from Alogliptin through pharmacophore hybridization and lead optimization
  作者：Hui Xie、Lili Zeng、Shaogao Zeng、Xin Lu、Xin Zhao、Guicheng Zhang、Zhengchao Tu、Hongjiang Xu、Ling Yang、Xiquan Zhang、Shanchun Wang、Wenhui Hu

  DOI：10.1016/j.ejmech.2013.08.010

  日期：2013.10

  The superposition of the DPP-IV complex revealed that the butynyl group of Linagliptin can be freely switched with the cyanobenzyl group of Alogliptin. Thus, a pharmacophore hybridization of Alogliptin was initiated and led to a novel DPP-IV inhibitor, 11a. Although it did not exhibit the desired activity (IC50 = 0.2 mu M), compound 11a acts as a lead compound, which triggered a resulting structural optimization and the formation of compound 11m. A novel series of potent DPP-IV inhibitors represented by compound 11m (IC50 = 0.4 nM) was ultimately obtained with a robust pharmacokinetic profile and superior in vitro and in vivo efficacy compared to Alogliptin. (C) 2013 Elsevier Masson SAS. All rights reserved.