2-amino-6-(3-chlorobenzyl)-5-isopropyl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one | 1335027-02-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并嘧啶类
• 英文名称: 2-amino-6-(3-chlorobenzyl)-5-isopropyl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one
• 英文别名: 2-amino-6-[(3-chlorophenyl)methyl]-5-isopropyl-4H-[1,2,4]triazolo[5,1-b]pyrimidin-7-one；2-amino-6-[(3-chlorophenyl)methyl]-5-propan-2-yl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one
• CAS: 1335027-02-5
• 化学式: C₁₅H₁₆ClN₅O
• 分子量: 317.778
• InChiKey: CHNSDJOKVUZBQF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  83.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  3,5-二氨基-1,2,4-三氮唑 、 ethyl 2-(3-chlorobenzyl)-4-methyl-3-oxopentanoate 在 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate 作用下， 反应 1.0h， 以21%的产率得到2-amino-6-(3-chlorobenzyl)-5-isopropyl[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

文献信息

• [EN] 4H- [1, 2, 4] TRIAZOLO [5, 1 -B] PYRIMIDIN-7 -ONE DERIVATIVES AS CCR2B RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS DE 4H-[1,2,4]TRIAZOLO[5,1-B]PYRIMIDIN-7-ONE À TITRE D'ANTAGONISTES DES RÉCEPTEURS CCR2B
  申请人：ASTRAZENECA AB

  公开号：WO2011114148A1

  公开（公告）日：2011-09-22

  The present invention relates to novel compounds for use in the compositions, to processes for their preparation, to intermediates useful in their preparation and to their use as therapeutic agents. The present invention also relates to pharmaceutical compositions, which comprise compounds that act via antagonism of the CCR2b receptor for which MCP-1 is one of the known ligands and so may be used to treat inflammatory disease, atherosclerosis, diabetes, obesity, cancer, chronic obstructive pulmonary disease (COPD) rheumatoid arthritis and/or neuropathic pain, which is mediated by these receptors.

  本发明涉及用于组合物中的新化合物，用于它们的制备过程，用于它们的制备中有用的中间体以及它们作为治疗剂的用途。本发明还涉及包含通过对CCR2b受体的拮抗作用而起作用的化合物的药物组合物，其中MCP-1是已知的配体之一，因此可用于治疗由这些受体介导的炎症性疾病、动脉粥样硬化、糖尿病、肥胖症、癌症、慢性阻塞性肺病（COPD）、类风湿性关节炎和/或由这些受体介导的神经病痛。
• 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.