1-(but-2-yn-1-yl)-6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione | 1470077-17-8

• 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: 1-(but-2-yn-1-yl)-6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione
• 英文别名: 1-(but-2-ynyl)-6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione；1-But-2-ynyl-6-chloro-3-methylpyrimidine-2,4-dione；1-but-2-ynyl-6-chloro-3-methylpyrimidine-2,4-dione
• CAS: 1470077-17-8
• 化学式: C₉H₉ClN₂O₂
• 分子量: 212.636
• InChiKey: ZNVJFFNUJNLJIV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-(R)-aminopiperidine dihydrochloride 、 1-(but-2-yn-1-yl)-6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione 在 碳酸氢钠 作用下， 以 乙硫醇 为溶剂， 反应 2.0h， 以65.2%的产率得到(R)-6-(3-aminopiperidin-1-yl)-1-(but-2-yn-1-yl)-3-methylpyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Highly potent dipeptidyl peptidase IV inhibitors derived from Alogliptin through pharmacophore hybridization and lead optimization

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2013.08.010
• 作为产物：
  描述：

  1-(but-2-ynyl)-6-chloropyrimidine-2,4(1H,3H)-dione 、 碘甲烷 在 sodium hydride 、 lithium bromide 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 0.41h， 以98%的产率得到1-(but-2-yn-1-yl)-6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Highly potent dipeptidyl peptidase IV inhibitors derived from Alogliptin through pharmacophore hybridization and lead optimization

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2013.08.010

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.
• Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin
  作者：Zeng-Wei Lai、Chunhong Li、Jun Liu、Lingyi Kong、Xiaoan Wen、Hongbin Sun

  DOI：10.1016/j.ejmech.2014.06.044

  日期：2014.8

  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.