N-(6-(2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamido)hexyl)-3,4-bis(4-methoxyphenyl)isoxazole-5-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N-(6-(2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamido)hexyl)-3,4-bis(4-methoxyphenyl)isoxazole-5-carboxamide
• 英文别名: N,N’-(hexane-1,6-diyl)bis{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamide}；2-[3,4-bis(4-methoxyphenyl)-1,2-oxazol-5-yl]-N-[6-[[2-[3,4-bis(4-methoxyphenyl)-1,2-oxazol-5-yl]acetyl]amino]hexyl]acetamide
• 化学式: C₄₄H₄₆N₄O₈
• 分子量: 758.871
• InChiKey: QHWYAGZZGGOAJP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  56
• 可旋转键数：
  19
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  147
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  1,6-己二胺 、 莫非佐酸 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 二氯甲烷 为溶剂， 反应 18.0h， 以25%的产率得到N-(6-(2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamido)hexyl)-3,4-bis(4-methoxyphenyl)isoxazole-5-carboxamide
  参考文献：
  名称：

  An attempt to chemically state the cross-talk between monomers of COX homodimers by double/hybrid inhibitors mofezolac-spacer-mofezolac and mofezolac-spacer-arachidonic acid

  摘要：

  Cardiovascular diseases (CVDs) account for over 17 million death globally each year, including arterial thrombosis. Platelets are key components in the pathogenesis of this disease and modulating their activity is an effective strategy to treat such thrombotic events. Cyclooxygenase-1 (COX-1) isoenzyme is involved in platelet activation and is the main target of non-steroidal anti-inflammatory drugs (NSAIDs) and new selective inhibitor research. Inhibitors of general formula mofezolac-spacer-mofezolac (mof-spacer-mof) and mofezolac-spacer-arachidonic acid (mof-spacer-AA) were projected to investigate the possible cross-talk between the two monomers (Eallo and Ecat) forming the COX-1 homodimer. Mofezolac was chosen as either one or two moieties of these molecules being the known most potent and selective COX-1 inhibitor and administrated to humans as Disopain™, then arachidonic acid (AA) was used to develop molecules bearing, in the same compound, in addition to the inhibitor moiety (mofezolac) also the natural COX substrate. Depending on the nature of the spacer, COX-1 and COX-2 activity was differently inhibited by mof-spacer-mof set with a preferential COX-1 inhibition. The highest COX-1 selectivity was exhibited by the compound in which the spacer was the benzidine [N,N'-(biphenyl-4,4'-di-yl)bis (2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamide) (15): COX-1 IC50 = 0.08 μM, COX-2 IC50 > 50 μM, Selectivity Index (SI) > 625]. In the case of mof-spacer-AA set, the COX inhibitory potency and also the isoform preference changed. (5Z, 8Z, 11Z, 14Z)-N-(4-{2-[3,4-Bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}butyl)icosa-5,8,11,14-tetraenamide (19) and (5Z, 8Z, 11Z, 14Z)-N-(4'-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}-[1,1'-biphenyl]-4-yl)icosa-5,8,11,14-tetraenamide (21), in which the spacer is the 1,2-diaminobutane or benzidine, respectively, selectively inhibited the COX-2, whereas when the spacer is the 1,4-phenylendiamine [(5Z, 8Z, 11Z, 14Z)-N-(4-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}phenyl)icosa-5,8,11,14-tetraenamide) (20) the COX preference is COX-1 (COX-1 IC50 = 0.05 μM, COX-2 IC50 > 50 μM, with a COX-1 selectivity > 1000). Molecular modelling by using FLAP algorithm shows fundamental interactions of the novel compounds at the entry channel of COX and inside its catalytic cavity. The effect of these mof-spacer-mof and mof-spacer-AA in inhibiting in vitro free arachidonic acid-induced platelet aggregation was also determined. A positive profile of hemocompatibility in relation to their influence on the blood coagulation cascade and erythrocyte toxicity was observed. Cytotoxicity and genotoxicity safety were also found for these two novel sets of compounds.

  DOI：

  10.1016/j.ejmech.2020.112919

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。
• An attempt to chemically state the cross-talk between monomers of COX homodimers by double/hybrid inhibitors mofezolac-spacer-mofezolac and mofezolac-spacer-arachidonic acid
  作者：Maria Grazia Perrone、Morena Miciaccia、Paola Vitale、Savina Ferorelli、Cristina da Costa Bernardes Araújo、Gabriella Silva de Almeida、Thaisa Francielle Souza Domingos、Luiz Claudio Rodrigues Pereira da Silva、Marcelo de Pádula、Lucio Mendes Cabral、Plínio Cunha Sathler、Carmela Bonaccorso、Cosimo G. Fortuna、Antonio Scilimati

  DOI：10.1016/j.ejmech.2020.112919

  日期：2021.1

  Cardiovascular diseases (CVDs) account for over 17 million death globally each year, including arterial thrombosis. Platelets are key components in the pathogenesis of this disease and modulating their activity is an effective strategy to treat such thrombotic events. Cyclooxygenase-1 (COX-1) isoenzyme is involved in platelet activation and is the main target of non-steroidal anti-inflammatory drugs (NSAIDs) and new selective inhibitor research. Inhibitors of general formula mofezolac-spacer-mofezolac (mof-spacer-mof) and mofezolac-spacer-arachidonic acid (mof-spacer-AA) were projected to investigate the possible cross-talk between the two monomers (Eallo and Ecat) forming the COX-1 homodimer. Mofezolac was chosen as either one or two moieties of these molecules being the known most potent and selective COX-1 inhibitor and administrated to humans as Disopain™, then arachidonic acid (AA) was used to develop molecules bearing, in the same compound, in addition to the inhibitor moiety (mofezolac) also the natural COX substrate. Depending on the nature of the spacer, COX-1 and COX-2 activity was differently inhibited by mof-spacer-mof set with a preferential COX-1 inhibition. The highest COX-1 selectivity was exhibited by the compound in which the spacer was the benzidine [N,N'-(biphenyl-4,4'-di-yl)bis (2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamide) (15): COX-1 IC50 = 0.08 μM, COX-2 IC50 > 50 μM, Selectivity Index (SI) > 625]. In the case of mof-spacer-AA set, the COX inhibitory potency and also the isoform preference changed. (5Z, 8Z, 11Z, 14Z)-N-(4-2-[3,4-Bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}butyl)icosa-5,8,11,14-tetraenamide (19) and (5Z, 8Z, 11Z, 14Z)-N-(4'-2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}-[1,1'-biphenyl]-4-yl)icosa-5,8,11,14-tetraenamide (21), in which the spacer is the 1,2-diaminobutane or benzidine, respectively, selectively inhibited the COX-2, whereas when the spacer is the 1,4-phenylendiamine [(5Z, 8Z, 11Z, 14Z)-N-(4-2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}phenyl)icosa-5,8,11,14-tetraenamide) (20) the COX preference is COX-1 (COX-1 IC50 = 0.05 μM, COX-2 IC50 > 50 μM, with a COX-1 selectivity > 1000). Molecular modelling by using FLAP algorithm shows fundamental interactions of the novel compounds at the entry channel of COX and inside its catalytic cavity. The effect of these mof-spacer-mof and mof-spacer-AA in inhibiting in vitro free arachidonic acid-induced platelet aggregation was also determined. A positive profile of hemocompatibility in relation to their influence on the blood coagulation cascade and erythrocyte toxicity was observed. Cytotoxicity and genotoxicity safety were also found for these two novel sets of compounds.