tert-butyl 3-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: tert-butyl 3-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate
• 化学式: C₁₅H₂₅NO₅
• 分子量: 299.367
• InChiKey: CDKCUTDILXXPHL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  21
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl 3-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate 、 N³-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-4H-1,2,4-triazole-3,5-diamine 在 sodium ethanolate 作用下， 以 乙醇 为溶剂， 反应 0.1h， 生成
  参考文献：
  名称：

  作为选择性 NLRP3 炎症小体抑制剂的三唑并嘧啶酮衍生物的发现和优化

  摘要：

  NLRP3 炎症小体是一种多蛋白复合物，可促进促炎细胞因子白介素-1β (IL-1β) 和 IL-18 响应感染或内源性刺激而激活和释放。它可能被一系列危险信号不当激活，导致多种疾病的慢性、低度炎症，如阿尔茨海默病、帕金森病、骨关节炎和痛风。有效且特异性的 NLRP3 抑制剂的发现可以减轻几种常见疾病的负担。在这项研究中，我们在计算机建模练习后发现了一种弱效的三唑并嘧啶酮 ( 1 ) 。经过优化，可提供有效且选择性的小分子 NLRP3 炎性体抑制剂。NDT-30805等化合物可能是支架跳跃或药效团生成项目的有用工具分子，或用作临床候选药物开发的先导。

  DOI：

  10.1021/acsmedchemlett.2c00242
• 作为产物：
  描述：

  ethyl potassium malonate 、 1-BOC-哌啶-3-羧酸 在 N,N'-羰基二咪唑 、 magnesium chloride 作用下， 以 乙腈 为溶剂， 反应 17.0h， 以86%的产率得到tert-butyl 3-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate
  参考文献：
  名称：

  Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration Models

  摘要：

  Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications.

  DOI：

  10.1021/jm5013984

文献信息

• Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration Models
  作者：Snahel Patel、Frederick Cohen、Brian J. Dean、Kelly De La Torre、Gauri Deshmukh、Anthony A. Estrada、Arundhati Sengupta Ghosh、Paul Gibbons、Amy Gustafson、Malcolm P. Huestis、Claire E. Le Pichon、Han Lin、Wendy Liu、Xingrong Liu、Yichin Liu、Cuong Q. Ly、Joseph P. Lyssikatos、Changyou Ma、Kimberly Scearce-Levie、Young G. Shin、Hilda Solanoy、Kimberly L. Stark、Jian Wang、Bei Wang、Xianrui Zhao、Joseph W. Lewcock、Michael Siu

  DOI：10.1021/jm5013984

  日期：2015.1.8

  Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications.
• Discovery and Optimization of Triazolopyrimidinone Derivatives as Selective NLRP3 Inflammasome Inhibitors
  作者：David Harrison、Mark G. Bock、John R. Doedens、Christopher A. Gabel、M. Katharine Holloway、Arwel Lewis、Jane Scanlon、Andrew Sharpe、Iain D. Simpson、Pamela Smolak、Grant Wishart、Alan P. Watt

  DOI：10.1021/acsmedchemlett.2c00242

  日期：2022.8.11

  osteoarthritis, and gout. The discovery of potent and specific NLRP3 inhibitors could reduce the burden of several common morbidities. In this study, we identified a weakly potent triazolopyrimidone hit (1) following an in silico modeling exercise. This was optimized to furnish potent and selective small molecule NLRP3 inflammasome inhibitors. Compounds such as NDT-30805 could be useful tool molecules

  NLRP3 炎症小体是一种多蛋白复合物，可促进促炎细胞因子白介素-1β (IL-1β) 和 IL-18 响应感染或内源性刺激而激活和释放。它可能被一系列危险信号不当激活，导致多种疾病的慢性、低度炎症，如阿尔茨海默病、帕金森病、骨关节炎和痛风。有效且特异性的 NLRP3 抑制剂的发现可以减轻几种常见疾病的负担。在这项研究中，我们在计算机建模练习后发现了一种弱效的三唑并嘧啶酮 ( 1 ) 。经过优化，可提供有效且选择性的小分子 NLRP3 炎性体抑制剂。NDT-30805等化合物可能是支架跳跃或药效团生成项目的有用工具分子，或用作临床候选药物开发的先导。