(R)-7-羟基华法林 | 63740-76-1

• 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: (R)-7-羟基华法林
• 英文名称: R-7-hydroxywarfarin
• 英文别名: (+)-7-hydroxywarfarin；[14C]-(R)-7-Hydroxywarfarin；(R)-7-Hydroxywarfarin；4,7-dihydroxy-3-[(1R)-3-oxo-1-phenylbutyl]chromen-2-one
• CAS: 63740-76-1
• 化学式: C₁₉H₁₆O₅
• 分子量: 324.333
• InChiKey: SKFYEJMLNMTTJA-OAHLLOKOSA-N

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

4,7-二羟基-3-[(1R)-3-氧代-1-苯基丁基]香豆素-2-酮是已知的人类代谢物，属于(R)-华法林。

4,7-dihydroxy-3-[(1R)-3-oxo-1-phenylbutyl]chromen-2-one is a known human metabolite of (R)-warfarin.

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 、 (R)-7-羟基华法林 在 UDP-glucuronosyltransferase 、 alamethicin I 、 magnesium chloride 作用下， 以 aq. buffer 为溶剂， 反应 1.0h， 生成 R-7-hydroxywarfarin β-D-4-glucuronide 、 R-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：

  (R)-(+)-杀鼠灵 在 NADPH-generating system 、 recombinant human cytochrome P₄₅₀ or CYP enzymes 、 维生素 D3 作用下， 以 phosphate buffer 为溶剂， 生成 (R)-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.
• 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：——
• Effects of arachidonic acid, prostaglandins, retinol, retinoic acid and cholecalciferol on xenobiotic oxidations catalysed by human cytochrome P450 enzymes
  作者：H. YAMAZAKI

  DOI：10.1080/004982599238632

  日期：1999.1

  inhibited slightly the xenobiotic oxidations catalysed by CYP1B1, 2B6, 2C9, 2D6, 2E1 and 3A4 in recombinant enzyme systems. 3. Retinol, retinoic acid and cholecalciferol were strong inhibitors for xenobiotic oxidations catalysed by recombinant CYP1A1, 2C8 and 2C19. 4. Dixon plots of inhibitions of CYP1A1-, 1A2-, 2C8- and 2C19-dependent xenobiotic oxidations by arachidonic acid, of CYP1A1-, 2B6- and 2C19-dependent

  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，
• Multiple UDP-glucuronosyltransferases in human liver microsomes glucuronidate both R- and S-7-hydroxywarfarin into two metabolites
  作者：C. Preston Pugh、Dakota L. Pouncey、Jessica H. Hartman、Robert Nshimiyimana、Linda P. Desrochers、Thomas E. Goodwin、Gunnar Boysen、Grover P. Miller

  DOI：10.1016/j.abb.2014.10.006

  日期：2014.12

  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.