tert-butyl 6-[(phenylcarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate | 1256449-23-6

• 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: tert-butyl 6-[(phenylcarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate
• CAS: 1256449-23-6
• 化学式: C₁₇H₂₂N₂O₃
• 分子量: 302.373
• InChiKey: CNHABDBPMKAYAE-WDNDVIMCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.28
• 重原子数：
  22.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  58.64
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  tert-butyl 6-[(phenylcarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate 在 盐酸 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 1.0h， 生成 ethyl 2-{6-[(phenylcarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxylate
  参考文献：
  名称：

  Discovery of 2-(6-{[(6-Fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a Class I Selective Orally Active Histone Deacetylase Inhibitor

  摘要：

  A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC50 values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.

  DOI：

  10.1021/jm101177s
• 作为产物：
  描述：

  (1α,5α,6α)-6-Nitro-3-azabicyclo[3.1.0]hexane hydrochloride 在 吡啶 、 4-二甲氨基吡啶 、 10% palladium on activated carbon 、 氢气 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 18.0h， 生成 tert-butyl 6-[(phenylcarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate
  参考文献：
  名称：

  Discovery of 2-(6-{[(6-Fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a Class I Selective Orally Active Histone Deacetylase Inhibitor

  摘要：

  A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC50 values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.

  DOI：

  10.1021/jm101177s

文献信息

• Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability
  作者：Rama Karadsheh、Megan E. Meuser、Simon Cocklin

  DOI：10.3390/molecules25061430

  日期：——

  Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal—to design an entry inhibitor with improved drug-like qualities—and warrants expanded studies to achieve this.

  Fostemsavir/temsavir是一种正在进行晚期临床试验的研究性HIV-1进入抑制剂。尽管它有望成为临床上首个以Env为靶点的进入抑制剂，但生物利用度方面的问题使其仅限于用于挽救治疗。因此，开发一种可以用于标准联合抗逆转录病毒疗法（cART）的小分子HIV-1进入抑制剂仍然是该领域的长期目标。我们先前证明了扩展该类抑制剂可用化学类别的能力是实现这一总体目标的第一步。除了溶解度不佳外，代谢稳定性是生物利用度的关键决定因素。因此，在这篇简短的通讯中，我们评估了我们的五种新型化学类别进入抑制剂的代谢稳定性。我们发现，改变temsavir的哌嗪核心区域会改变化合物在人肝微粒体测定中的稳定性。此外，我们发现了一种进入抑制剂，其代谢稳定性是temsavir的两倍以上，并证明了核心替换的取向对于这种增加是至关重要的。这项工作进一步证明了我们的长期目标的可行性——设计一种具有改进药物特性的进入抑制剂，并有必要展开更广泛的研究来实现这一目标。