phospho-sulindac | 1118973-90-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚和异茚
• 英文名称: phospho-sulindac
• 英文别名: OXT-238；4-diethoxyphosphoryloxybutyl 2-[(3Z)-6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]inden-1-yl]acetate
• CAS: 1118973-90-2
• 化学式: C₂₈H₃₄FO₇PS
• 分子量: 564.612
• InChiKey: DTBSJPFGPBZPHE-UQQQWYQISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  38
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  107
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  phospho-sulindac 在 flavin monooxygenase 1 、 还原型辅酶II(NADPH)四钠盐 作用下， 反应 20.0h， 生成 phospho-sulindac sulfone
  参考文献：
  名称：

  Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety

  摘要：

  BACKGROUND AND PURPOSEPhospho‐ibuprofen (MDC‐917) and phospho‐sulindac (OXT‐328) are highly effective in cancer and arthritis treatment in preclinical models. Here, we investigated their metabolism by major human cytochrome P450s (CYPs) and flavin monooxygenases (FMOs).EXPERIMENTAL APPROACHThe CYP/FMO‐catalysed metabolism of phospho‐ibuprofen and phospho‐sulindac was studied by using in silico prediction modelling and a direct experimental approach.KEY RESULTSThe CYP isoforms catalyse the oxidation of non‐steroidal anti‐inflammatory drugs (NSAIDs) and phospho‐NSAIDs, with distinct activity and regioselectivity. CYP1A2, 2C19, 2D6 and 3A4 oxidize phospho‐ibuprofen, but not ibuprofen; whereas CYP2C9 oxidizes ibuprofen, but not phospho‐ibuprofen. All CYPs tested oxidize phospho‐sulindac, but not sulindac. Among the five CYPs evaluated, CYP3A4 and 2D6 are the most active in the oxidation of phospho‐ibuprofen and phospho‐sulindac respectively. FMOs oxidized phospho‐sulindac and sulindac, but not phospho‐ibuprofen or ibuprofen. FMOs were more active towards phospho‐sulindac than sulindac, indicating that phospho‐sulindac is a preferred substrate of FMOs. The susceptibility of phospho‐NSAIDs to CYP/FMO‐mediated metabolism was also reflected in their rapid oxidation by human and mouse liver microsomes, which contain a full complement of CYPs and FMOs. Compared with conventional NSAIDs, the higher activity of CYPs towards phospho‐ibuprofen and phospho‐sulindac may be due to their greater lipophilicity, a key parameter for CYP binding.CONCLUSIONS AND IMPLICATIONSCYPs and FMOs play an important role in the metabolism of phospho‐NSAIDs, resulting in differential pharmacokinetic profiles between phospho‐NSAIDs and NSAIDs in vivo. The consequently more rapid detoxification of phospho‐NSAIDs is likely to contribute to their greater safety.

  DOI：

  10.1111/j.1476-5381.2012.01982.x

文献信息

• PHOSPHO-ESTER DERIVATIVES AND USES THEREOF
  申请人：RIGAS Basil

  公开号：US20130225529A1

  公开（公告）日：2013-08-29

  Phospho-ester compounds and pharmaceutical compositions thereof administered by the respiratory and other routes for the prevention and/or treatment of lung and brain cancer and precancerous conditions thereof, for the treatment of pain, for the treatment of skin disorders, for treating and/or preventing inflammation-related diseases, and for the treatment and prevention of cancer.

  磷酸酯化合物及其制剂可通过呼吸道及其他途径用于预防和/或治疗肺癌和脑癌及其癌前病变条件，用于疼痛治疗，用于皮肤疾病治疗，用于治疗和/或预防与炎症相关的疾病，以及用于癌症的治疗和预防。
• [EN] ANTI-INFLAMMATORY COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS ANTI-INFLAMMATOIRES ET LEURS UTILISATIONS
  申请人：RIGAS BASIL

  公开号：WO2009023631A1

  公开（公告）日：2009-02-19

  Compounds of the general Formula (I) are disclosed with activity towards treating diseases related to inflammation, such as cancer, neurodegenerative and cardiovascular diseases. Pharmaceutical compositions and methods of use are also described.

  揭示了通式（I）的化合物，具有治疗与炎症相关的疾病，如癌症、神经退行性和心血管疾病的活性。还描述了制药组合物和使用方法。
• COMPOUNDS AND COMPOSITIONS FOR USE IN THE TREATMENT AND PREVENTION OF LUNG AND BRAIN CANCER AND PRECANCEROUS CONDITIONS THEREOF
  申请人：Medicon Pharmaceuticals, Inc.

  公开号：US20140178461A1

  公开（公告）日：2014-06-26

  Novel compounds and pharmaceutical compositions thereof administered by the respiratory route for prevention and/or treatment of lung and brain cancer and precancerous conditions thereof.

  通过呼吸道给予的新化合物和其制药组合物，用于预防和/或治疗肺癌、脑癌及其癌前状态。
• Product Comprising a Nicotine-Containing Material and an Anti-Cancer Agent
  申请人：Rigas, Basil

  公开号：EP2711006A1

  公开（公告）日：2014-03-26

  The invention is directed to a product comprising a nicotine-containing material and an anti-cancer agent. The product is applicable in the treatment and/or prevention of cancer and precancerous conditions as well as for preventing cancer recurrence.

  本发明涉及一种由含尼古丁材料和抗癌剂组成的产品。该产品适用于治疗和/或预防癌症和癌前病变，以及预防癌症复发。
• METHODS AND COMPOSITIONS FOR THE TREATMENT OF VASCULAR MALFORMATION
  申请人：IFOM Fondazione Istituto Firc di Oncologia Molecolare

  公开号：EP3145547A1

  公开（公告）日：2017-03-29