1,3-diphenethylpyrimidine-2,4,6(1H,3H,5H)-trione | 496839-76-0

• 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: 1,3-diphenethylpyrimidine-2,4,6(1H,3H,5H)-trione
• 英文别名: 1,3-bis(2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione；1,3-bis(2-phenylethyl)-1,3-diazinane-2,4,6-trione
• CAS: 496839-76-0
• 化学式: C₂₀H₂₀N₂O₃
• mdl: MFCD02380118
• 分子量: 336.39
• InChiKey: HSNSQMGDNFKEES-UHFFFAOYSA-N

物化性质

• 沸点：
  500.2±53.0 °C(Predicted)
• 密度：
  1.224±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  57.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1,3-diphenethylpyrimidine-2,4,6(1H,3H,5H)-trione 在 sodium ethanolate 、 三氯氧磷 作用下， 反应 14.0h， 生成 6-methoxy-1,3-diphenethylpyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Pyrimidine-2,4,6-trione Derivatives and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation. Toward a Treatment for Amyotrophic Lateral Sclerosis

  摘要：

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. The only FDA-approved drug for the treatment of ALS, riluzole, only extends the median survival in patients by 2-3 months. There is an urgent need for novel therapeutic strategies for this devastating disease. Using a high-throughput screening assay targeting an ALS cultured cell model (PC12-G93A-YFP cell line), we previously identified three chemotypes that were neuroprotective. We present a further detailed analysis of one promising scaffold from that group, pyrimidine-2,4,6-triones (PYTs), characterizing a number of PYT analogues using SAR and ADME. The PYT compounds show good potency, superior ADME data, low toxicity, brain penetration, and excellent oral bioavailability. Compounds from this series show 100% efficacy in the protection assay with a good correlation in activity between the protection and protein aggregation assays. The modifications of the PYT scaffold presented here suggest that this chemical structure may be a novel drug candidate scaffold for use in clinical trials in ALS.

  DOI：

  10.1021/jm101549k
• 作为产物：
  描述：

  2-苯乙胺 在 乙酸酐 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 28.5h， 生成 1,3-diphenethylpyrimidine-2,4,6(1H,3H,5H)-trione
  参考文献：
  名称：

  Pyrimidine-2,4,6-trione Derivatives and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation. Toward a Treatment for Amyotrophic Lateral Sclerosis

  摘要：

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. The only FDA-approved drug for the treatment of ALS, riluzole, only extends the median survival in patients by 2-3 months. There is an urgent need for novel therapeutic strategies for this devastating disease. Using a high-throughput screening assay targeting an ALS cultured cell model (PC12-G93A-YFP cell line), we previously identified three chemotypes that were neuroprotective. We present a further detailed analysis of one promising scaffold from that group, pyrimidine-2,4,6-triones (PYTs), characterizing a number of PYT analogues using SAR and ADME. The PYT compounds show good potency, superior ADME data, low toxicity, brain penetration, and excellent oral bioavailability. Compounds from this series show 100% efficacy in the protection assay with a good correlation in activity between the protection and protein aggregation assays. The modifications of the PYT scaffold presented here suggest that this chemical structure may be a novel drug candidate scaffold for use in clinical trials in ALS.

  DOI：

  10.1021/jm101549k

文献信息

• Development of a Polo-like Kinase-1 Polo-Box Domain Inhibitor as a Tumor Growth Suppressor in Mice Models
  作者：Pethaiah Gunasekaran、Min Su Yim、Mija Ahn、Nak-Kyun Soung、Jung-Eun Park、Jaehi Kim、Geul Bang、Sang Chul Shin、Joonhyeok Choi、Minkyoung Kim、Hak Nam Kim、Young-Ho Lee、Young-Ho Chung、Kyeong Lee、Eunice EunKyeong Kim、Young-Ho Jeon、Min Ju Kim、Kyeong-Ryoon Lee、Bo-Yeon Kim、Kyung S. Lee、Eun Kyoung Ryu、Jeong Kyu Bang

  DOI：10.1021/acs.jmedchem.0c01451

  日期：2020.12.10

  Polo-like kinase-1 (Plk1) plays a key role in mitosis and has been identified as an attractive anticancer drug target. Plk1 consists of two drug-targeting sites, namely, N-terminal kinase domain (KD) and C-terminal polo-box domain (PBD). As KD-targeting inhibitors are associated with severe side effects, here we report on the pyrazole-based Plk1 PBD inhibitor, KBJK557, which showed a remarkable in vitro anticancer effect by inducing Plk1 delocalization, mitotic arrest, and apoptosis in HeLa cells. Further, in vivo optical imaging analysis and antitumorigenic activities in mouse xenograft models demonstrate that KBJK557 preferentially accumulates in cancer cells and selectively inhibits cancer cell proliferation. Pharmacokinetic profiles and partition coefficients suggest that KBJK557 was exposed in the blood and circulated through the organs with an intermediate level of clearance (t_1/2, 7.73 h). The present investigation offers a strategy for specifically targeting cancer using a newly identified small-molecule inhibitor that targets the Plk1 PBD.
• [EN] PYRIMIDINE-2,4,6-TRIONES FOR USE IN THE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS<br/>[FR] PYRIMIDINE-2,4,6-TRIONES DESTINÉE À ÊTRE UTILISÉE POUR LE TRAITEMENT D'UNE SCLÉROSE LATÉRALE AMYOTROPHE
  申请人：CAMBRIA PHARMACEUTICALS INC

  公开号：WO2010129665A3

  公开（公告）日：2011-04-07
• PYRIMIDINE-2,4,6-TRIONES FOR USE IN THE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS
  申请人：Cambria Pharmaceuticals, Inc.

  公开号：EP2427438B1

  公开（公告）日：2016-10-12
• FLAVOR COMPOSITIONS AND PET FOOD PRODUCTS CONTAINING THE SAME
  申请人：Mars, Incorporated

  公开号：EP3229610B1

  公开（公告）日：2021-06-09
• SELECTIVE CALCIUM CHANNEL ANTAGONISTS
  申请人：Northwestern University

  公开号：US20160310491A1

  公开（公告）日：2016-10-27

  The present invention relates to compositions and methods for the treatment and/or prevention of neurodegenerative disorders, e.g., Parkinson's disease (PD). In particular, the present invention provides compositions comprising selective antagonists of calcium ion channels (e.g., cav1.3-type ion channels), and methods of use thereof to treat or prevent neurodegenerative disorders.