2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetic acid | 1579976-83-2

• 分子结构分类: 有机化合物 - 有机卤素化合物 - 芳基卤化物
• 英文名称: 2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetic acid
• 英文别名: 2-[3-(5-Chlorofuran-2-yl)-4-phenyl-1,2-oxazol-5-yl]acetic acid；2-[3-(5-chlorofuran-2-yl)-4-phenyl-1,2-oxazol-5-yl]acetic acid
• CAS: 1579976-83-2
• 化学式: C₁₅H₁₀ClNO₄
• 分子量: 303.702
• InChiKey: AEJVPDNQHBVQTD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  76.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-叔丁氧羰基-1,4-丁二胺 、 2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以42%的产率得到tert-butyl (4-{2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetamido}butyl)carbamate
  参考文献：
  名称：

  基于异恶唑的脚手架抑制剂靶向环氧化酶（COX）

  摘要：

  探索了一套具有附加功能的新的环氧合酶（COX）抑制剂。这些新化合物还包含若丹明6G或6,7-二甲氧基-1,2,3,4-四氢异喹啉，分别是外排泵底物和抑制剂的两个典型部分。在所有合成的化合物中，发现了两种具有相反选择性的新型COX抑制剂：化合物8 [ N-（9- {2-[（4-{2- [3-（5-氯呋喃-2-基）-4-苯基异恶唑-5-基]乙酰胺基}丁基]氨基甲酰基]苯基-6-（乙基氨基）-2,7-二甲基-3 H-黄嘌呤-3-亚基}乙氯化铵]被发现是一种选择性的COX-1抑制剂，而17（2- [3,4-双（4-甲氧基苯基）异恶唑-5-基] -1- [6,7-二甲氧基-3,4-二氢异喹啉-2-（1 H）-基]乙酮）被发现是亚微摩尔选择性COX-2抑制剂。但是，两者均显示与P-糖蛋白相互作用。对接实验有助于阐明观察到的COX选择性的分子方面。

  DOI：

  10.1002/cmdc.201500439
• 作为产物：
  描述：

  2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetonitrile 在 水 、 对甲苯磺酸 、 potassium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 0.33h， 生成 2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetic acid
  参考文献：
  名称：

  Selective COX-1 inhibition as a target of theranostic novel diarylisoxazoles

  摘要：

  Cyclooxygenase(COX)-1 role in some diseases is increasingly studied. 3-(5-Chlorofuran-2-yl)-5-methy14-phenylisoxazole (P6), a highly selective cyclooxygenase-1 inhibitor, was used as a "lead" to design new isoxazoles (2a-m), differently selective towards COX-1. Those isoxazoles might be useful as novel theranostic agents and also to better clarify COX-1 role in the human physiology and diseases. 2a-m were prepared in fair to good yields developing suitable synthetic strategies. They were evaluated in vitro for their COX-inhibitory activity and selectivity. Structure activity relationship studies of the novel set of diarylisoxazoles allowed to identify new key determinants for COX-1 selectivity, and to uncover compounds appropriate for a deep pharmacokinetic and pharmacodynamic investigation. 3-(5-Chlorofuran2yl)-4-phenylisoxazol-5-amine (2f) was the most active compound of the series, its inhibitory activity was assessed in purified enzyme (COX-1 IC50 = 1.1 mu M; COX-2 IC50 > 50 mu M) and in the ovarian cancer cell line (OVCAR-3) expressing only COX-1 (IC50 = 0.58 mu M). Furthermore, the high inhibitory potency of 2f was rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-1 binding site. We found critical interactions between the inhibitor and constriction residues R120 and Y355 at the base of the active site, as well as with S530 at the top of the side pocket. (C) 2014 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2013.12.023

文献信息

• [EN] MOFEZOLAC DERIVATIVES AS MULTI-FUNCTIONS SELECTIVE COX-1 INHIBITORS<br/>[FR] DÉRIVÉS DE MOFÉZOLAC EN TANT QU'INHIBITEURS SÉLECTIFS À FONCTIONS MULTIPLES DE COX-1
  申请人：UNIVERSITA' DEGLI STUDI DI BARI ALDO MORO

  公开号：WO2017187352A1

  公开（公告）日：2017-11-02

  The invention relates to a new class of compounds of formula (I) targeting COX-1. The invention also relates to the use of some of such compounds as a tool to investigate the structure and function of the enzyme, in the treatment targeting COX-1 or detection of COX-1 in relating disorders or diseases such as cancer and neuroinflammation, in particular in neurological (e.g. autism spectrum disorders) and neurodegenerative diseases (e.g. Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), HIV dementia and prion diseases), and in gynecological tumour (e.g. ovarian cancer), neck and head tumor, and haematological tumours (e.g. multiple myeloma) and in the detection of COX-1 in "in vitro" (cells and tissues) and in "in vivo".

  本发明涉及一类新的化合物，其化学式为（I），用于靶向COX-1。本发明还涉及使用其中一些化合物作为研究该酶的结构和功能的工具，在治疗靶向COX-1或检测与癌症和神经炎症等相关的疾病或疾病中的COX-1，特别是在神经学（例如自闭症谱系障碍）和神经退行性疾病（例如阿尔茨海默病，帕金森病，肌萎缩性侧索硬化症（ALS），多发性硬化症（MS），创伤性脑损伤（TBI），HIV痴呆和朊病）以及妇科肿瘤（例如卵巢癌），颈部和头部肿瘤和血液系统肿瘤（例如多发性骨髓瘤）和检测“体外”（细胞和组织）和“体内”的COX-1。
• MOFEZOLAC DERIVATIVES AS MULTI-FUNCTIONS SELECTIVE COX-1 INHIBITORS
  申请人：Università degli Studi di Bari "Aldo Moro"

  公开号：EP3782990A1

  公开（公告）日：2021-02-24

  The invention relates to a new class of compounds targeting COX-1. The invention also relates to the use of some of such compounds as a tool to investigate the structure and function of the enzyme, in the treatment targeting COX-1 or detection of COX-1 in relating disorders or diseases such as cancer and neuroinflammation, in particular in neurological (e.g. autism spectrum disorders) and neurodegenerative diseases (e.g. Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), HIV dementia and prion diseases), and in gynecological tumour (e.g. ovarian cancer), neck and head tumor, and haematological tumours (e.g. multiple myeloma) and in the detection of COX-1 in "in vitro" (cells and tissues) and in "in vivo".

  本发明涉及一类靶向 COX-1 的新型化合物。本发明还涉及将其中一些化合物用作研究酶的结构和功能的工具，用于靶向 COX-1 的治疗或检测 COX-1 在癌症和神经炎症等相关紊乱或疾病中的作用，特别是在神经系统疾病（如自闭症谱系障碍）和神经退行性疾病（如阿尔茨海默病、帕金森病、肌萎缩性侧索硬化症（ALS）、多发性硬化症（MLS））中的作用。阿尔茨海默病、帕金森病、肌萎缩性脊髓侧索硬化症（ALS）、多发性硬化症（MS）、创伤性脑损伤（TBI）、艾滋病痴呆症和朊病毒病），以及妇科肿瘤（如卵巢癌）、颈部和头部肿瘤和血液肿瘤（如多发性骨髓瘤），以及在 "体外"（细胞和组织）和 "体内 "检测 COX-1。
• Selective COX-1 inhibition as a target of theranostic novel diarylisoxazoles
  作者：Paola Vitale、Maria Grazia Perrone、Paola Malerba、Antonio Lavecchia、Antonio Scilimati

  DOI：10.1016/j.ejmech.2013.12.023

  日期：2014.3

  Cyclooxygenase(COX)-1 role in some diseases is increasingly studied. 3-(5-Chlorofuran-2-yl)-5-methy14-phenylisoxazole (P6), a highly selective cyclooxygenase-1 inhibitor, was used as a "lead" to design new isoxazoles (2a-m), differently selective towards COX-1. Those isoxazoles might be useful as novel theranostic agents and also to better clarify COX-1 role in the human physiology and diseases. 2a-m were prepared in fair to good yields developing suitable synthetic strategies. They were evaluated in vitro for their COX-inhibitory activity and selectivity. Structure activity relationship studies of the novel set of diarylisoxazoles allowed to identify new key determinants for COX-1 selectivity, and to uncover compounds appropriate for a deep pharmacokinetic and pharmacodynamic investigation. 3-(5-Chlorofuran2yl)-4-phenylisoxazol-5-amine (2f) was the most active compound of the series, its inhibitory activity was assessed in purified enzyme (COX-1 IC50 = 1.1 mu M; COX-2 IC50 > 50 mu M) and in the ovarian cancer cell line (OVCAR-3) expressing only COX-1 (IC50 = 0.58 mu M). Furthermore, the high inhibitory potency of 2f was rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-1 binding site. We found critical interactions between the inhibitor and constriction residues R120 and Y355 at the base of the active site, as well as with S530 at the top of the side pocket. (C) 2014 Published by Elsevier Masson SAS.
• Isoxazole-Based-Scaffold Inhibitors Targeting Cyclooxygenases (COXs)
  作者：Maria Grazia Perrone、Paola Vitale、Andrea Panella、Savina Ferorelli、Marialessandra Contino、Antonio Lavecchia、Antonio Scilimati

  DOI：10.1002/cmdc.201500439

  日期：2016.6.6

  A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline, two moieties typical of efflux pump substrates and inhibitors, respectively. Among all the synthesized compounds, two new COX inhibitors with opposite selectivity were discovered: compound 8 [N‐(9

  探索了一套具有附加功能的新的环氧合酶（COX）抑制剂。这些新化合物还包含若丹明6G或6,7-二甲氧基-1,2,3,4-四氢异喹啉，分别是外排泵底物和抑制剂的两个典型部分。在所有合成的化合物中，发现了两种具有相反选择性的新型COX抑制剂：化合物8 [ N-（9- 2-[（4-2- [3-（5-氯呋喃-2-基）-4-苯基异恶唑-5-基]乙酰胺基}丁基]氨基甲酰基]苯基-6-（乙基氨基）-2,7-二甲基-3 H-黄嘌呤-3-亚基}乙氯化铵]被发现是一种选择性的COX-1抑制剂，而17（2- [3,4-双（4-甲氧基苯基）异恶唑-5-基] -1- [6,7-二甲氧基-3,4-二氢异喹啉-2-（1 H）-基]乙酮）被发现是亚微摩尔选择性COX-2抑制剂。但是，两者均显示与P-糖蛋白相互作用。对接实验有助于阐明观察到的COX选择性的分子方面。