[14C]-6-Hydroxyastemizole | 90836-19-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: [14C]-6-Hydroxyastemizole
• 英文别名: 6-Hydroxyastemizole；3-[(4-Fluorophenyl)methyl]-2-[[1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl]amino]benzimidazol-5-ol
• CAS: 90836-19-4
• 化学式: C₂₈H₃₁FN₄O₂
• 分子量: 474.578
• InChiKey: GJJYAIIDIMCSIM-UHFFFAOYSA-N

物化性质

• 沸点：
  667.5±65.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  62.6
• 氢给体数：
  2
• 氢受体数：
  6

ADMET

代谢

6-羟基阿司咪唑是人代谢阿司咪唑的已知形式。

6-Hydroxyastemizole is a known human metabolite of astemizole.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  阿司咪唑 在 cytochrome P₄₅₀ BM₃ variant T₂₆₀L 作用下， 反应 1.0h， 以100%的产率得到[14C]-6-Hydroxyastemizole
  参考文献：
  名称：

  一组细胞色素 P450 BM3 变体用于生产药物代谢物并使先导化合物多样化

  摘要：

  在此，我们证明来自巨大芽孢杆菌的细胞色素 P450 BM3 的一小部分变体通过产生两种市售药物维拉帕米和阿司咪唑以及一种研究化合物的 13 种哺乳动物代谢物中的 12 种，涵盖了人类 P450 的反应范围。最活跃的酶支持制备单个代谢物以进行临床前生物活性和毒理学评估。工程化的 P450 BM3 变体还强调了其在药物先导多样化方面的潜在用途，通过催化碳中心的反应，产生超出动物和人类 P450 靶向范围的反应，从而产生新的代谢物。通过酶催化剂的定向进化可以改善特定代谢物的产生。一些变体对疏水性更强的母体药物比其代谢物更活跃，这限制了多羟基化物质的产生，这种偏好似乎取决于 P450 变体的进化历史。

  DOI：

  10.1002/chem.200900643

文献信息

• Characterization of the Active Site Properties of CYP4F12
  作者：John Eksterowicz、Dan A. Rock、Brooke M. Rock、Larry C. Wienkers、Robert S. Foti

  DOI：10.1124/dmd.114.059626

  日期：2014.10

  Cytochrome P450 4F12 is a drug-metabolizing enzyme that is primarily expressed in the liver, kidney, colon, small intestine, and heart. The properties of CYP4F12 that may impart an increased catalytic selectivity (decreased promiscuity) were explored through in vitro metabolite elucidation, kinetic isotope effect experiments, and computational modeling of the CYP4F12 active site. By using astemizole as a probe substrate for CYP4F12 and CYP3A4, it was observed that although CYP4F12 favored astemizole O -demethylation as the primary route of metabolism, CYP3A4 was capable of metabolizing astemizole at multiple sites on the molecule. Deuteration of astemizole at the site of O -demethylation resulted in an isotope effect of 7.1 as well as an 8.3-fold decrease in the rate of clearance for astemizole by CYP4F12. Conversely, although an isotope effect of 3.8 was observed for the formation of the O -desmethyl metabolite when deuterated astemizole was metabolized by CYP3A4, there was no decrease in the clearance of astemizole. Development of a homology model of CYP4F12 based on the crystal structure of cytochrome P450 BM3 predicted an active site volume for CYP4F12 that was approximately 76% of the active site volume of CYP3A4. As predicted, multiple favorable binding orientations were available for astemizole docked into the active site of CYP3A4, but only a single binding orientation with the site of O -demethylation oriented toward the heme was identified for CYP4F12. Overall, it appears that although CYP4F12 may be capable of binding similar ligands to other cytochrome P450 enzymes such as CYP3A4, the ability to achieve catalytically favorable orientations may be inherently more difficult because of the increased steric constraints of the CYP4F12 active site.

  细胞色素 P450 4F12 是一种药物代谢酶，主要在肝脏、肾脏、结肠、小肠和心脏中表达。通过体外代谢物阐释、动力学同位素效应实验以及对 CYP4F12 活性位点的计算建模，研究人员探索了 CYP4F12 可提高催化选择性（降低杂交性）的特性。通过使用阿司咪唑作为 CYP4F12 和 CYP3A4 的探针底物，观察到虽然 CYP4F12 更倾向于将阿司咪唑 O -去甲基化作为主要代谢途径，但 CYP3A4 能够在分子的多个位点代谢阿司咪唑。在 O -去甲基化位点对阿司咪唑进行氚化会产生 7.1 的同位素效应，并使 CYP4F12 对阿司咪唑的清除率降低 8.3 倍。相反，虽然氚化阿司咪唑经 CYP3A4 代谢后形成的 O - 去甲基代谢物的同位素效应为 3.8，但阿司咪唑的清除率并没有降低。根据细胞色素 P450 BM3 晶体结构建立的 CYP4F12 同源模型预测，CYP4F12 的活性位点体积约为 CYP3A4 活性位点体积的 76%。正如预测的那样，阿司咪唑与 CYP3A4 的活性位点对接后有多个有利的结合方向，但 CYP4F12 只确定了一个单一的结合方向，即 O -去甲基化位点朝向血红素。总的看来，虽然 CYP4F12 可能能够与其他细胞色素 P450 酶（如 CYP3A4）的类似配体结合，但由于 CYP4F12 活性位点的立体限制增加，实现有利催化取向的能力本质上可能更加困难。
• TARGET PROTEIN AND TARGET GENE IN DRUG DESIGNING AND SCREENING METHOD
  申请人：Yamauchi Tadakazu

  公开号：US20100136524A1

  公开（公告）日：2010-06-03

  The present invention provides a novel target protein and a gene for drug discovery, and a means that enables development of a novel pharmaceutical agent by using the same. More particularly, the present invention provides CARP and genes thereof; screening methods for drugs (e.g., antiallergic drugs); a regulator of diseases (e.g., allergic diseases); a drug derivative production method; a complex comprising a drug and CARP, and a production method thereof; kits comprising a drug or a salt thereof; determination methods for the onset or risk of onset of a specified disease, determination methods for susceptibility to a drug, and determination kits used for said methods, and the like.
• US8153385B2
  申请人：——

  公开号：US8153385B2

  公开（公告）日：2012-04-10
• A Panel of Cytochrome P450 BM3 Variants to Produce Drug Metabolites and Diversify Lead Compounds
  作者：Andrew M. Sawayama、Michael M. Y. Chen、Palaniappan Kulanthaivel、Ming-Shang Kuo、Horst Hemmerle、Frances H. Arnold

  DOI：10.1002/chem.200900643

  日期：2009.11.2

  cytochrome P450 BM3 from Bacillus megaterium covers the breadth of reactivity of human P450s by producing 12 of 13 mammalian metabolites for two marketed drugs, verapamil and astemizole, and one research compound. The most active enzymes support preparation of individual metabolites for preclinical bioactivity and toxicology evaluations. Underscoring their potential utility in drug lead diversification, engineered

  在此，我们证明来自巨大芽孢杆菌的细胞色素 P450 BM3 的一小部分变体通过产生两种市售药物维拉帕米和阿司咪唑以及一种研究化合物的 13 种哺乳动物代谢物中的 12 种，涵盖了人类 P450 的反应范围。最活跃的酶支持制备单个代谢物以进行临床前生物活性和毒理学评估。工程化的 P450 BM3 变体还强调了其在药物先导多样化方面的潜在用途，通过催化碳中心的反应，产生超出动物和人类 P450 靶向范围的反应，从而产生新的代谢物。通过酶催化剂的定向进化可以改善特定代谢物的产生。一些变体对疏水性更强的母体药物比其代谢物更活跃，这限制了多羟基化物质的产生，这种偏好似乎取决于 P450 变体的进化历史。