(+)-5-Hydroxypropranolol | 91796-22-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (+)-5-Hydroxypropranolol
• 英文别名: (R)-5-hydroxypropranolol；5-[(2R)-2-hydroxy-3-(propan-2-ylamino)propoxy]naphthalen-1-ol
• CAS: 91796-22-4
• 化学式: C₁₆H₂₁NO₃
• 分子量: 275.348
• InChiKey: WMYPGILKDMWISO-GFCCVEGCSA-N

物化性质

• 沸点：
  487.5±35.0 °C(Predicted)
• 密度：
  1.168±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  61.7
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (R)-1-(异丙基氨基)-3-(1-萘氧基)-2-丙醇盐酸 在 glucose 6-phosphate 、 G-6-P dehydrogenase 、 烟酰胺腺嘌呤双核苷酸磷酸盐 、 magnesium chloride 作用下， 生成 (+)-5-Hydroxypropranolol 、 (R)-N-desisopropylpropranolol 、 4-[(2R)-2-羟基-3-[(1-甲基乙基)氨基]丙氧基]-1-萘酚
  参考文献：
  名称：

  Regio- and stereoselective oxidation of propranolol enantiomers by human CYP2D6, cynomolgus monkey CYP2D17 and marmoset CYP2D19

  摘要：

  Toxic and pharmacokinetic profiles of drug candidates are evaluated in vivo often using monkeys as experimental animals, and the data obtained are extrapolated to humans. Well understanding physiological properties, including drug-metabolizing enzymes, of monkeys should increase the accuracy of the extrapolation. The present study was performed to compare regio- and stereoselectivity in the oxidation of propranolol (PL), a chiral substrate, by cytochrome P450 2D (CYP2D) enzymes among humans, cynomolgus monkeys and marmosets. Complimentary DNAs encoding human CYP2D6, cynomolgus monkey CYP2D17 and marmoset CYP2D19 were cloned, and their proteins expressed in a yeast cell expression system. The regio- and stereoselective oxidation of PL enantiomers by yeast cell microsomal fractions were compared. In terms of efficiency of expression in the system, the bob-proteins ranked CYP2D6=CYP2D17 >> CYP2D19. This may be caused by the bulky side chain of the amino acid residue at position 119 (leucine for CYP2D19 vs. valine for CYP2D6 and CYP2D17), which can disturb the incorporation of the heme moiety into the active-site cavity. PL enantiomers were oxidized by all of the enzymes mainly into 4-hydroxyproranolol (4-OH-PL), followed by 5-OH-PL and N-desisopropylpropranolol (NDP). In the kinetic analysis, apparent K(m) values were commonly in the mu M range and substrate enantioselectivity of R-PL < S-PL was observed in both K(m) and V values for the formation of the three metabolites from PL enantiomers. The activity to produce NEW tended to be higher for the monkey enzymes, particularly CYP2D17, than for the human enzyme. These results indicate that in the oxidation of PL enantiomers by CYP2D enzymes, stereoselectivity is similar but regioselectivity is different between humans and monkeys. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

  DOI：

  10.1016/j.cbi.2010.12.014

文献信息

• Regio- and stereoselective oxidation of propranolol enantiomers by human CYP2D6, cynomolgus monkey CYP2D17 and marmoset CYP2D19
  作者：Shizuo Narimatsu、Toshiyuki Nakata、Takeshi Shimizudani、Kenjiro Nagaoka、Hironori Nakura、Kazufumi Masuda、Takashi Katsu、Akiko Koeda、Shinsaku Naito、Shigeru Yamano、Atsuro Miyata、Nobumitsu Hanioka

  DOI：10.1016/j.cbi.2010.12.014

  日期：2011.2

  Toxic and pharmacokinetic profiles of drug candidates are evaluated in vivo often using monkeys as experimental animals, and the data obtained are extrapolated to humans. Well understanding physiological properties, including drug-metabolizing enzymes, of monkeys should increase the accuracy of the extrapolation. The present study was performed to compare regio- and stereoselectivity in the oxidation of propranolol (PL), a chiral substrate, by cytochrome P450 2D (CYP2D) enzymes among humans, cynomolgus monkeys and marmosets. Complimentary DNAs encoding human CYP2D6, cynomolgus monkey CYP2D17 and marmoset CYP2D19 were cloned, and their proteins expressed in a yeast cell expression system. The regio- and stereoselective oxidation of PL enantiomers by yeast cell microsomal fractions were compared. In terms of efficiency of expression in the system, the bob-proteins ranked CYP2D6=CYP2D17 >> CYP2D19. This may be caused by the bulky side chain of the amino acid residue at position 119 (leucine for CYP2D19 vs. valine for CYP2D6 and CYP2D17), which can disturb the incorporation of the heme moiety into the active-site cavity. PL enantiomers were oxidized by all of the enzymes mainly into 4-hydroxyproranolol (4-OH-PL), followed by 5-OH-PL and N-desisopropylpropranolol (NDP). In the kinetic analysis, apparent K(m) values were commonly in the mu M range and substrate enantioselectivity of R-PL < S-PL was observed in both K(m) and V values for the formation of the three metabolites from PL enantiomers. The activity to produce NEW tended to be higher for the monkey enzymes, particularly CYP2D17, than for the human enzyme. These results indicate that in the oxidation of PL enantiomers by CYP2D enzymes, stereoselectivity is similar but regioselectivity is different between humans and monkeys. (C) 2010 Elsevier Ireland Ltd. All rights reserved.