7-羟基华法林 | 63740-81-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 中文名称: 7-羟基华法林
• 中文别名: 7-羟基文拉法辛
• 英文名称: (S)-7-Hydroxywarfarin
• 英文别名: 7-hydroxy-S-warfarin；7-hydroxywarfarin；[13C]-(S)-7-Hydroxywarfarin；4,7-dihydroxy-3-[(1S)-3-oxo-1-phenylbutyl]chromen-2-one
• CAS: 63740-81-8
• 化学式: C₁₉H₁₆O₅
• 分子量: 324.333
• InChiKey: SKFYEJMLNMTTJA-HNNXBMFYSA-N

物化性质

• 熔点：
  220 °C
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  83.8
• 氢给体数：
  2
• 氢受体数：
  5

ADMET

代谢

7-羟基华法林已知的人类代谢物包括华法林7-O-葡萄糖苷酸。

7-Hydroxywarfarin has known human metabolites that include Warfarin 7-O-glucuronide.

来源:NORMAN Suspect List Exchange

反应信息

• 作为反应物：
  描述：

  6-[[[5-(2,4-二氧代嘧啶-1-基)-3,4-二羟基四氢呋喃-2-基]甲氧基-羟基磷酰]氧基-羟基磷酰]氧基-3,4,5-三羟基四氢吡喃-2-羧酸 、 7-羟基华法林 在 UDP-glucuronosyltransferase 、 alamethicin I 、 糖质酸-1,4-内酯 作用下， 以 aq. buffer 为溶剂， 反应 1.0h， 生成 S-7-hydroxywarfarin β-D-4-glucuronide 、 S-4-hydroxywarfarin β-D-7-glucuronide
  参考文献：
  名称：

  Multiple UDP-glucuronosyltransferases in human liver microsomes glucuronidate both R- and S-7-hydroxywarfarin into two metabolites

  摘要：

  The widely used anticoagulant Coumadin (R/S-warfarin) undergoes oxidation by cytochromes P450 into hydroxywarfarins that subsequently become conjugated for excretion in urine. Hydroxywarfarins may modulate warfarin metabolism transcriptionally or through direct inhibition of cytochromes P450 and thus, UGT action toward hydroxywarfarin elimination may impact levels of the parent drugs and patient responses. Nevertheless, relatively little is known about conjugation by UDP-glucuronosyltransferases in warfarin metabolism. Herein, we identified probable conjugation sites, kinetic mechanisms and hepatic UGT isoforms involved in microsomal glucuronidation of R-and S-7-hydroxywarfarin. Both compounds underwent glucuronidation at C4 and C7 hydroxyl groups based on elution properties and spectral characteristics. Their formation demonstrated regio-and enantioselectivity by UGTs and resulted in either Michaelis-Menten or substrate inhibition kinetics. Glucuronidation at the C7 hydroxyl group occurred more readily than at the C4 group, and the reaction was overall more efficient for R-7-hydroxywarfarin due to higher affinity and rates of turnover. The use of these mechanisms and parameters to model in vivo clearance demonstrated that contributions of substrate inhibition would lead to underestimation of metabolic clearance than that predicted by Michaelis-Menten kinetics. Lastly, these processes were driven by multiple UGTs indicating redundancy in glucuronidation pathways and ultimately metabolic clearance of R-and S-7-hydroxywarfarin. (C) 2014 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.abb.2014.10.006
• 作为产物：
  描述：

  (S)-(-)-华法令 在 human cytochrome P₄₅₀ or CYP enzymes or liver microsomes 、 NADPH-generating system 、 维生素A 作用下， 以 phosphate buffer 为溶剂， 生成 7-羟基华法林
  参考文献：
  名称：

  花生四烯酸，前列腺素，视黄醇，视黄酸和胆钙化固醇对人细胞色素P450酶催化的异种生物氧化的影响。

  摘要：

  1.研究了花生四烯酸，前列腺素，视黄醇，视黄酸和胆钙化固醇对12种重组人细胞色素P450（P450或CYP）酶和人肝微粒体催化的异种生物氧化的影响。2.花生四烯酸（50 microM）显着抑制CYP1A1和1A2依赖性7-乙氧基香豆素O-去乙基化，CYP2C8依赖性紫杉醇6α-羟基化和CYP2C19依赖性R-华法林7-羟基化。在重组酶系统中，该化学物质还略微抑制了CYP1B1、2B6、2C9、2D6、2E1和3A4催化的异种生物氧化。3.视黄醇，视黄酸和胆钙化醇是重组CYP1A1、2C8和2C19催化的异种生物氧化的强抑制剂。[4]。花生四烯酸对CYP1A1-，1A2-，2C8-和2C19依赖性异生素氧化的抑制作用的狄克逊图，视黄醇对CYP1A1、2B6和2C19的依赖性，以及胆钙化醇对CYP1A1和2C19的依赖性，表明这些化学物质主要通过竞争机制抑制P450的活性。5.在人肝微粒体中，

  DOI：

  10.1080/004982599238632

文献信息

• Ultrafast chiral separations for high throughput enantiopurity analysis
  作者：Chandan L. Barhate、Leo A. Joyce、Alexey A. Makarov、Kerstin Zawatzky、Frank Bernardoni、Wes A. Schafer、Daniel W. Armstrong、Christopher J. Welch、Erik L. Regalado

  DOI：10.1039/c6cc08512a

  日期：——

  Ultrafast chiral chromatography enables high throughput enantiopurity analysis (over one thousand samples in an 8 h workday) for enantioselective synthesis investigations.

  超快手性色谱法实现了高通量对映体纯度分析（8 小时工作日内可分析一千多个样品），用于对映体选择性合成研究。
• Roles of two allelic variants (Arg144Cys and Ile359Leu) of cytochrome P4502C9 in the oxidation of tolbutamide and warfarin by human liver microsomes
  作者：H. YAMAZAKI、K. INOUE、T. SHIMADA

  DOI：10.1080/004982598239614

  日期：1998.1

  1. Tolbutamide methyl hydroxylation and racemic warfarin 7-hydroxylation activities were determined in liver microsomes of 39 Japanese and 45 Caucasians genotyped for the cytochrome P450 (P450 or CYP) 2C9 gene into three groups, namely the wild-type (Arg144.Ile359), and two heterozygous Cys allele (Cys144.Ile359) and Leu allele (Arg144.Leu359) variants.2. Good correlations were found between tolbutamide methyl hydroxylation and racemic warfarin 7-hydroxylation activities in liver microsomes of Japanese and Caucasians. Humans with the Cys allele CYP2C9 variant, which was detected in 22% of Caucasians, were found to have similar catalytic rates to those of the wild-type in the oxidations of tolbutamide and racemic warfarin, whereas humans with the Leu allele, which was detected in 8% Japanese and 7% Caucasian samples, had lower catalytic rates than those of other two groups.3. The rates of 6- and 7-hydroxylation of racemic warfarin were correlated well with those of S-warfarin, but not R-warfarin, in human liver microsomes.4. Both human liver microsomes and recombinant CYP2C9 catalysed 7-hydroxylation of S-warfarin more extensively than those of R-warfarin. K-m's for the 7-hydroxylation of S-warfarin were not very different in liver microsomes of humans with these three genotypes. Anti-CYP2C9 antibodies and sulphaphenazole inhibited the 6- and 7-hydroxylation of S-warfarin, but not R-warfarin, by > 90% and the methyl hydroxylation of tolbutamide by about 50%.5. These results suggest that humans with Leu allele of CYP2C9 have lower V-max's for S-warfarin 7-hydroxylation and tolbutamide methyl hydroxylation than those with wildtype and Cys allele CYP2C9, although the K-m's are not very different in liver microsomes of these three groups of humans. R-warfarin hydroxylation may be catalysed by P450 enzymes other than CYP2C9 in man.
• Characterization of mixtures of recombinant human cytochrome P450s as a screening model for metabolic stability in drug discovery
  作者：N. Hagen、A. K. Olsen、J. V. Andersen、J. Tjørnelund、S. H. Hansen

  DOI：10.1080/00498250210147124

  日期：2002.1

  1. Recombinant human cytochrome P450 (rhCYP) has become an important screening model in drug metabolism studies due to the high cost of human and animal hepatic tissue. Until now, rhCYPs have been evaluated and used as separate forms, but a mixture of CYP forms comparable with the human liver could be of value in early drug discovery.2. In the present study, rhCYP2C9, rhCYP2D6 and rhCYP3A4 co-expressed with reductase in Escerichia coli were mixed and evaluated with regards to kinetic properties (K-m and V-max). Furthermore, antioxidant was added to investigate whether a free radical scavenger would affect the kinetic parameters. Results were compared with data obtained in human liver microsomes (HLM).3. Results showed a good correlation between mixed rhCYP data and HLM data for K-m and V-max. K-m varied < 3-fold between matrices for CYP2C9 and CYP3A4, whereas the K-m for CYP2D6 varied up to 4.5-fold. V-max differed up to 3-fold between matrices for the CYP forms investigated. However, the discrepancy in Vmax may depend on the anticipated level of each form in HLM. The addition of antioxidant increased Vmax for CYP2C9 and CYP2D6 by 75 and 50%, respectively, whereas V-max for CYP3A4 was unchanged.4. In conclusion, the rhCYP mixture shows promising results as a predictor of CYP kinetic parameters. Furthermore, addition of antioxidant can in certain cases increase catalytic activity.
• Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes
  作者：A. Hemeryck、C. De Vriendt、F. M. Belpaire

  DOI：10.1007/s002280050580

  日期：1999.2.22

  Objective: To investigate the in vitro potential of selective serotonin reuptake inhibitors (SSRIs) to inhibit two CYP2C9-catalysed reactions, tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation.Methods: The formation of 4-hydroxytolbutamide from tolbutamide and that of 7-hydroxywarfarin from (S)warfarin as a function of different concentrations of SSRIs and some of their metabolites was studied in microsomes from three human livers.Results: Both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation followed one enzyme Michaelis-Menten kinetics. Kinetic analysis of 4-hydroxytolbutamide formation yielded a mean apparent Michaelis-Menten constant (K-m) of 133 mu M and a mean apparent maximal velocity (V-max) of 248 pmol.min(-1).mg(-1) formation of 7-hydroxywarfarin yielded a mean K-m of 3.7 mu M and a mean V-max of 10.5 pmol.min(-1).mg(-1) Amongst the SSRIs and some of their metabolites tested, only fluvoxamine markedly inhibited both reactions. The average computed inhibition constant (K-i) values and ranges of fluvoxamine when tolbutamide and (S)-warfarin were used as substrate, were 13.3 (6.4-17.3) mu M and 13.0 (8.4-18.7) mu M, respectively; The average Ki value of fluoxetine for (S)-warfarin 7-hydroxylation was 87.0 (57.0-125) mu M.Conclusion: Amongst the SSRIs tested, fluvoxamine was shown to be the most potent inhibitor of both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. Fluoxetine, norfluoxetine, paroxetine, sertraline, desmethylsertraline, citalopram, desmethylcitalopram had little or no effect on CYP2C9 activity in vitro. This is consistent with in vivo data indicating that amongst the SSRIs, fluvoxamine has the greatest potential for inhibiting CYP2C9-mediated drug metabolism.
• HEIMARK, L. D.;TRAGER, W. F., J. MED. CHEM., 1985, 28, N 4, 503-506
  作者：HEIMARK, L. D.、TRAGER, W. F.

  DOI：——

  日期：——