6-Amino-2-(biphenyl-4-ylmethylsulfanyl)-pyrimidin-4-ol

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 6-Amino-2-(biphenyl-4-ylmethylsulfanyl)-pyrimidin-4-ol
• 英文别名: 4-amino-2-[(4-phenylphenyl)methylsulfanyl]-1H-pyrimidin-6-one
• 化学式: C₁₇H₁₅N₃OS
• 分子量: 309.392
• InChiKey: UILOIZNPVUATLC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  92.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-Amino-2-(biphenyl-4-ylmethylsulfanyl)-pyrimidin-4-ol 在 碳酸甲丙酯 、 三氯氧磷 作用下， 以9%的产率得到2-(Biphenyl-4-ylmethylsulfanyl)-6-chloro-pyrimidin-4-ylamine
  参考文献：
  名称：

  Pyrimidine Thioethers:  A Novel Class of HIV-1 Reverse Transcriptase Inhibitors with Activity Against BHAP-Resistant HIV

  摘要：

  A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded several analogues, which demonstrated activity against both enzyme types, with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation of a select number of pyrimidine thioethers in cell culture showed that these compounds have excellent activity against HIV-1(IIIB)-WT and retain good activity against a laboratory-derived HIV-1(MF) delavirdine-resistant variant.

  DOI：

  10.1021/jm9800806
• 作为产物：
  描述：

  4-溴甲基联苯 、 6-氨基-2-硫脲嘧啶 在 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 反应 17.0h， 生成 6-Amino-2-(biphenyl-4-ylmethylsulfanyl)-pyrimidin-4-ol
  参考文献：
  名称：

  Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists

  摘要：

  Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.11.111

文献信息

• Pyrimidine Thioethers:  A Novel Class of HIV-1 Reverse Transcriptase Inhibitors with Activity Against BHAP-Resistant HIV
  作者：Richard A. Nugent、Stephen T. Schlachter、Michael J. Murphy、Gary J. Cleek、Toni J. Poel、Donn G. Wishka、David R. Graber、Yoshihiko Yagi、Barbara J. Keiser、Robert A. Olmsted、Laurie A. Kopta、Steven M. Swaney、Susan M. Poppe、Joel Morris、W. Gary Tarpley、Richard C. Thomas

  DOI：10.1021/jm9800806

  日期：1998.9.1

  A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded several analogues, which demonstrated activity against both enzyme types, with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation of a select number of pyrimidine thioethers in cell culture showed that these compounds have excellent activity against HIV-1(IIIB)-WT and retain good activity against a laboratory-derived HIV-1(MF) delavirdine-resistant variant.
• Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists
  作者：Hanh Nho Nguyen、Howie Bregman、John L. Buchanan、Bingfan Du、Elma Feric、Liyue Huang、Xingwen Li、Joseph Ligutti、Dong Liu、Annika B. Malmberg、David J. Matson、Jeff S. McDermott、Vinod F. Patel、Ben Wilenkin、Anruo Zou、Stefan I. McDonough、Erin F. DiMauro

  DOI：10.1016/j.bmcl.2011.11.111

  日期：2012.1

  Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties. (C) 2011 Elsevier Ltd. All rights reserved.