ethyl 3-cyclopropyl-3-oxo-2-{[3-(trifluoromethyl)phenyl]methyl}propanoate | 1370227-58-9

• 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: ethyl 3-cyclopropyl-3-oxo-2-{[3-(trifluoromethyl)phenyl]methyl}propanoate
• 英文别名: ethyl 3-cyclopropyl-3-oxo-2-(3-(trifluoromethyl)benzyl)-propanoate；Ethyl 3-cyclopropyl-3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]propanoate；ethyl 3-cyclopropyl-3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]propanoate
• CAS: 1370227-58-9
• 化学式: C₁₆H₁₇F₃O₃
• 分子量: 314.304
• InChiKey: QPNXXNFDGZIEFP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3,5-二氨基-1,2,4-三氮唑 、 ethyl 3-cyclopropyl-3-oxo-2-{[3-(trifluoromethyl)phenyl]methyl}propanoate 在 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate 作用下， 反应 1.0h， 以6%的产率得到2-amino-5-cyclopropyl-6-(3-(trifluoromethyl)benzyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one
  参考文献：
  名称：

  Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5

  摘要：

  CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the highly conserved intracellular binding site in chemokine receptors provides a new avenue for the design of multitarget ligands. In this study, we synthesized and evaluated the biological activity of a series of triazolopyrimidinone derivatives in CCR2 and CCR5. Radioligand binding assays first showed that they bind to the intracellular site of CCR2, and in combination with functional assays on CCR5, we explored structure-affinity/activity relationships in both receptors. Although most compounds were CCR2-selective, 39 and 43 inhibited beta-arrestin recruitment in CCR5 with high potency. Moreover, these compounds displayed an insurmountable mechanism of inhibition in both receptors, which holds promise for improved efficacy in inflammatory diseases.

  DOI：

  10.1021/acs.jmedchem.9b00742
• 作为产物：
  描述：

  3-(三氟甲基)溴苄 、 3-环丙基-3-羰基-丙酸乙酯 在 N,N-二异丙基乙胺 、 lithium chloride 作用下， 以 四氢呋喃 为溶剂， 反应 20.0h， 以31%的产率得到ethyl 3-cyclopropyl-3-oxo-2-{[3-(trifluoromethyl)phenyl]methyl}propanoate
  参考文献：
  名称：

  Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5

  摘要：

  CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the highly conserved intracellular binding site in chemokine receptors provides a new avenue for the design of multitarget ligands. In this study, we synthesized and evaluated the biological activity of a series of triazolopyrimidinone derivatives in CCR2 and CCR5. Radioligand binding assays first showed that they bind to the intracellular site of CCR2, and in combination with functional assays on CCR5, we explored structure-affinity/activity relationships in both receptors. Although most compounds were CCR2-selective, 39 and 43 inhibited beta-arrestin recruitment in CCR5 with high potency. Moreover, these compounds displayed an insurmountable mechanism of inhibition in both receptors, which holds promise for improved efficacy in inflammatory diseases.

  DOI：

  10.1021/acs.jmedchem.9b00742

文献信息

• 7-HYDROXY-PYRAZOLO[1,5-A] PYRIMIDINE COMPOUNDS AND THEIR USE AS CCR2 RECEPTOR ANTAGONISTS
  申请人：Boyd Joe William

  公开号：US20130252951A1

  公开（公告）日：2013-09-26

  The compounds of formula (I) are antagonists of the CCR2 receptor Wherein R 1-7 and A are as defined in the claims.

  式(I)的化合物是CCR2受体的拮抗剂，其中R1-7和A如权利要求中所定义。
• Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5
  作者：Natalia V. Ortiz Zacarías、Jacobus P. D. van Veldhoven、Lisa S. den Hollander、Burak Dogan、Joseph Openy、Ya-Yun Hsiao、Eelke B. Lenselink、Laura H. Heitman、Adriaan P. IJzerman

  DOI：10.1021/acs.jmedchem.9b00742

  日期：2019.12.26

  CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the highly conserved intracellular binding site in chemokine receptors provides a new avenue for the design of multitarget ligands. In this study, we synthesized and evaluated the biological activity of a series of triazolopyrimidinone derivatives in CCR2 and CCR5. Radioligand binding assays first showed that they bind to the intracellular site of CCR2, and in combination with functional assays on CCR5, we explored structure-affinity/activity relationships in both receptors. Although most compounds were CCR2-selective, 39 and 43 inhibited beta-arrestin recruitment in CCR5 with high potency. Moreover, these compounds displayed an insurmountable mechanism of inhibition in both receptors, which holds promise for improved efficacy in inflammatory diseases.