5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione;pyrimidine-2,4-diol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione;pyrimidine-2,4-diol
• 化学式: C12H13FN4O5
• 分子量: 312.25
• InChiKey: DHMYGZIEILLVNR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.95
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  117
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

替加氟通过肝脏微粒体细胞色素P450酶，主要是CYP 2A6，生物激活为5-氟尿嘧啶。这种生物激活的特点是存在C-5'氧化和C-2'水解。5-氟尿嘧啶随后转化为其活性代谢物5-氟脱氧尿苷一磷酸和5-氟尿苷三磷酸。超过80%的给药剂量由于二氢吡啶脱氢酶的代谢而被消除。其他一些代谢产物包括3'-羟基替加氟、4'-羟基替加氟和二氢替加氟，它们都比5-氟尿嘧啶的细胞毒性小得多。

Tegafur is bioactivated to 5-fluorouracil by the liver microsomal cytochrome P450 enzymes, mainly the CYP 2A6. This bioactivation is marked by the presence of C-5' oxidation and C-2' hydrolysis. The 5-fluorouracil is later transformed into its active metabolite 5-fluorodeoxyuridine-monophosphate and 5-fluorouridine-triphosphate. More than 80% of the administered dose is eliminated due to the metabolism of dihydropyridine dehydrogenase. Some other metabolic products include 3'-hydroxy tegafur, 4'-hydroxy tegafur and dihydro tegafur which all of them are significantly less cytotoxic than 5-fluorouracil.

来源:DrugBank

毒理性

• 蛋白质结合

吉西他滨的血清结合蛋白为52%，而尿嘧啶的蛋白结合可以忽略不计。

The serum binding protein of tegafur is of 52% while the protein binding of uracil is negligible.

来源:DrugBank

吸收、分配和排泄

• 吸收

系统循环的吸收非常迅速，药峰浓度在1-2小时内达到。在单次剂量为300 mg/m2/天的 tegafur/尿嘧啶分三次给药后，tegafur的血浆浓度在整个8小时给药间隔内保持在>1000 ng/ml，而尿嘧啶的浓度在达到峰值浓度后迅速下降。5-氟尿嘧啶的血浆浓度在给药后30-60分钟达到峰值，为200 ng/ml，并且在8小时给药间隔内保持可检测。尿嘧啶、tegafur或5-氟尿嘧啶没有显著的长效积累。

The absorption into systemic circulation is very rapid and the peak concentration is reached within 1-2 hours. After a single dose of tegafur/uracil of 300 mg/m2/day in three divided doses, tegafur plasma concentration of >1000 ng/ml are maintained throughout the 8-hour dosing interval, whereas uracil concentrations decline rapidly following the peak concentration. The plasma concentration of 5-fluorouracil peaks at 30-60 min after administration with 200 ng/ml and remain detectable for 8-hour dosing interval. There is no significant long-term accumulation of either uracil, tegafur or 5-fluorouracil.

来源:DrugBank

吸收、分配和排泄

• 消除途径

经口服给药后，给药剂量的少于20%的替加氟以原形从尿中排出。

Less than 20% of the administered dose of tegafur is excreted intact in the urine following the oral administration.

来源:DrugBank

吸收、分配和排泄

• 分布容积

替加氟的分布容积据报道为59升，而尿嘧啶的分布容积为474升。

The volume of distribution of tegafur is reported to be 59 L while the uracil volume of distribution of 474 L.

来源:DrugBank

吸收、分配和排泄

• 清除

当以替加氟/尿嘧啶的形式给药时，报告的替加氟清除率范围为47至175毫升/分钟。

The reported clearance of tegafur when administered in the form of tegafur/uracil ranged from 47 to 175 ml/min

来源:DrugBank

文献信息

• [EN] METALLOENZYME INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS DE MÉTALLOENZYMES
  申请人：VPS 3 INC

  公开号：WO2018165520A1

  公开（公告）日：2018-09-13

  Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.

  提供具有HDAC6调节活性的化合物，以及通过HDAC6介导的治疗疾病、疾病或症状的方法。
• [EN] ASH1L INHIBITORS AND METHODS OF TREATMENT THEREWITH<br/>[FR] INHIBITEURS DE ASH1L ET MÉTHODES DE TRAITEMENT AU MOYEN DE CEUX-CI
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2017197240A1

  公开（公告）日：2017-11-16

  Provided herein are small molecule inhibitors of ASH1L activity and small molecules that facilitate ASH1L degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L.

  本文提供了ASH1L活性的小分子抑制剂，促进ASH1L降解的小分子以及它们的使用方法，用于治疗疾病，包括急性白血病、实体肿瘤和其他依赖于ASH1L活性的疾病。
• THERAPEUTIC COMPOUNDS AND COMPOSITIONS
  申请人：Salituro Francesco G.

  公开号：US20120172349A1

  公开（公告）日：2012-07-05

  Compounds and compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.

  本文描述了包含调节丙酮酸激酶M2（PKM2）的化合物和组合物。本文还描述了利用调节PKM2的化合物治疗癌症的方法。
• [EN] NOVEL N- (4- (AZETIDINE - 1 - CARBONYL) PHENYL) - (HETERO - ) ARYLSULFONAMIDE DERIVATIVES AS PYRUVATE KINASE M2 (PMK2) MODULATORS<br/>[FR] NOUVEAUX DÉRIVÉS DE N-(4-(AZÉTIDINE- 1 - CARBONYL) PHÉNYL)-(HÉTÉRO-) ARYLSULFONAMIDE EN TANT QUE MODULATEURS DE LA PYRUVATE KINASE M2 (PMK2)
  申请人：AGIOS PHARMACEUTICALS INC

  公开号：WO2012083246A1

  公开（公告）日：2012-06-21

  Compounds of general Formula (I), and compositions comprising compounds of general formula I that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.

  通用式(I)化合物和包含调节丙酮酸激酶M2（PKM2）的通用式I化合物的组合物在此处进行描述。此外，还描述了利用调节PKM2的化合物治疗癌症的方法。
• [EN] THERAPEUTIC COMPOUNDS AND COMPOSITIONS<br/>[FR] COMPOSÉS ET COMPOSITIONS THÉRAPEUTIQUES
  申请人：AGIOS PHARMACEUTICALS INC

  公开号：WO2014139325A1

  公开（公告）日：2014-09-18

  Compounds of general formula (I) and compositions comprising compounds of general formula (I) that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.

  本文描述了一般式（I）化合物和包含调节丙酮酸激酶的一般式（I）化合物的组合物。本文还描述了利用调节丙酮酸激酶的这些化合物治疗疾病的方法。