5-{4-[2-(2-吡啶基氨基)乙氧基]苄基}-1,3-噻唑烷-2,4-二酮 | 257892-31-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 5-{4-[2-(2-吡啶基氨基)乙氧基]苄基}-1,3-噻唑烷-2,4-二酮
• 中文别名: N-去甲罗格列酮
• 英文名称: N-Desmethylrosiglitazone
• 英文别名: N-desmethyl rosiglitazone；Rosiglitazon；5-[[4-[2-(pyridin-2-ylamino)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
• CAS: 257892-31-2
• 化学式: C₁₇H₁₇N₃O₃S
• 分子量: 343.406
• InChiKey: ZJQTVMXUIGXRMR-UHFFFAOYSA-N

物化性质

• 熔点：
  177-179°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)：
  3
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  6

ADMET

代谢

N-去甲基罗格列酮是罗格列酮已知的人类代谢物。

N-Desmethylrosiglitazone is a known human metabolite of rosiglitazone.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  罗格列酮 在 cytochrome P₄₅₀ reductase 、 cytochrome b5 、 cytochrome P₄₅₀ 2C₈ (Cyp₂C₈) wild type 、 还原型辅酶II(NADPH)四钠盐 作用下， 生成 5-{4-[2-(2-吡啶基氨基)乙氧基]苄基}-1,3-噻唑烷-2,4-二酮
  参考文献：
  名称：

  Drug metabolism by CYP2C8.3 is determined by substrate dependent interactions with cytochrome P450 reductase and cytochrome b5

  摘要：

  Genetic polymorphisms in CYP2C8 can influence the metabolism of important therapeutic agents and cause interindividual variation in drug response and toxicity. The significance of the variant CYP2C8*3 has been controversial with reports of higher in vivo but lower in vitro activity compared to CYP2C8*1. In this study, the contribution of the redox partners cytochrome P450 reductase (CPR) and cytochrome b5 to the substrate dependent activity of CYP2C8.3 (R139K, K399R) was investigated in human liver microsomes (HLMs) and Escherichia call expressed recombinant CYP2C8 proteins using amodiaquine, paclitaxel, rosiglitazone and cerivastatin as probe substrates. For recombinant CYP2C8.3, clearance values were two- to five-fold higher compared to CYP2C8.1. CYP2C8.3's higher k(cat) seems to be dominated by a higher, but substrate specific affinity, towards cytochrome b5 and CPR (K(D) and K(m,red)) which resulted in increased reaction coupling. A stronger binding affinity of ligands to CYP2C8.3, based on a two site binding model, in conjunction with a five fold increase in amplitude of heme spin change during binding of ligands and redox partners could potentially contribute to a higher k(cat), in HLMs, carriers of the CYP2C8*1/*3 genotype were as active as CYP2C8*1/*1 towards the CYP2C8 specific reaction amodiaquine N-deethylation. Large excess of cytochrome b5 compared to CYP2C8 in recombinant systems and HLMs inhibited metabolic clearance, diminishing the difference in k(cat) between the two enzymes, and may provide an explanation for the discrepancy to in vivo data. In silico studies illustrate the genetic differences between wild type and variant on the molecular level. (C) 2011 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2011.06.027

文献信息

• Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions
  申请人：Kõster Hubert

  公开号：US20100248264A1

  公开（公告）日：2010-09-30

  Capture compounds and collections thereof and methods using the compounds for the analysis of biomolecules are provided. In particular, collections, compounds and methods are provided for analyzing complex protein mixtures, such as the proteome. The compounds are multifunctional reagents that provide for the separation and isolation of complex protein mixtures. Automated systems for performing the methods also are provided.

  提供了捕获化合物及其集合以及使用这些化合物进行生物分子分析的方法。特别地，提供了用于分析复杂蛋白质混合物（如蛋白质组）的集合、化合物和方法。这些化合物是多功能试剂，可用于分离和分离复杂的蛋白质混合物。还提供了执行这些方法的自动化系统。
• [EN] SUBSTANTIALLY PURE ROSIGLITAZONE HYDROGEN SULFATE<br/>[FR] HYDROGÉNOSULFATE DE ROSIGLITAZONE ESSENTIELLEMENT PUR
  申请人：ACTAVIS GROUP PTC EHF

  公开号：WO2010013141A2

  公开（公告）日：2010-02-04

  Provided herein are impurities of rosiglitazone hydrogen sulfate, 4-[2-(N-methyl-2-(N- pyridinyl)amino)ethoxy]bromobenzene (bromo impurity) and 5-[[4-[2-[methyl-(2-pyridinyl- N-oxide)amino]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (N-oxide impurity), and processes for preparing and isolating thereof. Provided further herein is a highly pure rosiglitazone hydrogen sulfate substantially free of bromo and N-oxide impurities, process for the preparation thereof, and pharmaceutical compositions comprising highly pure rosiglitazone hydrogen sulfate substantially free of bromo and N-oxide impurities.
• [EN] INFLAMMATORY DISEASE TREATMENT<br/>[FR] TRAITEMENT DE MALADIES INFLAMMATOIRES
  申请人：PULMAGEN THERAPEUTICS INFLAMMATION LTD

  公开号：WO2011098801A1

  公开（公告）日：2011-08-18

  Compounds of formula (I) are useful in the treatment of inflammatory disease wherein at least 95% by weight of the said compound of formula (I) is in the stereoconfiguration shown in formula (IA) and less than 5% by weight is in the stereoconfiguration shown in formula (IB) in which formulae (I), (IA) and (IB): R is CH3- or hydrogen; X1 is -OR1, -S(O)nR2 or -NR3R4 and X2 is-OH; or X1 and X2 taken together represent a radical *-OC(O)NH-** or *-C(O)N(H)O-** wherein the bond marked * is attached to the carbon to which W and R are attached, and the bond marked ** is attached to the carbonyl carbon; R1 and R2 are independently C1-6 alkyl optionally substituted with one or more halogen atoms; C1-6 alkoxyalkyl; or aryl R3 and R4 are independently hydrogen; C1-6 alkyl; aryl; a group -C(Ra)=C(Rb)-C(=O)-Ara wherein Ra and Rb are independently hydrogen or C1-6 alkyl and Ara is aryl; or a group -Arb-C(=O)-Arc wherein Arb and Arc are aryl; or -C(=O)O-Rc wherein Rc is an aryl or C1-6alkyl; or R3 and R4 taken together with the nitrogen to which they are attached form a saturated ring of 3 to 7 ring members or an unsaturated ring of 5 to 7 ring members; n is 0,1 or 2; W is a group which when linked to the -C(R)(X1)C(=O)X2 results in a compound (I) having PPARγ agonist activity.
• Drug metabolism by CYP2C8.3 is determined by substrate dependent interactions with cytochrome P450 reductase and cytochrome b5
  作者：Rüdiger Kaspera、Suresh B. Naraharisetti、Eric A. Evangelista、Kristin D. Marciante、Bruce M. Psaty、Rheem A. Totah

  DOI：10.1016/j.bcp.2011.06.027

  日期：2011.9

  Genetic polymorphisms in CYP2C8 can influence the metabolism of important therapeutic agents and cause interindividual variation in drug response and toxicity. The significance of the variant CYP2C8*3 has been controversial with reports of higher in vivo but lower in vitro activity compared to CYP2C8*1. In this study, the contribution of the redox partners cytochrome P450 reductase (CPR) and cytochrome b5 to the substrate dependent activity of CYP2C8.3 (R139K, K399R) was investigated in human liver microsomes (HLMs) and Escherichia call expressed recombinant CYP2C8 proteins using amodiaquine, paclitaxel, rosiglitazone and cerivastatin as probe substrates. For recombinant CYP2C8.3, clearance values were two- to five-fold higher compared to CYP2C8.1. CYP2C8.3's higher k(cat) seems to be dominated by a higher, but substrate specific affinity, towards cytochrome b5 and CPR (K(D) and K(m,red)) which resulted in increased reaction coupling. A stronger binding affinity of ligands to CYP2C8.3, based on a two site binding model, in conjunction with a five fold increase in amplitude of heme spin change during binding of ligands and redox partners could potentially contribute to a higher k(cat), in HLMs, carriers of the CYP2C8*1/*3 genotype were as active as CYP2C8*1/*1 towards the CYP2C8 specific reaction amodiaquine N-deethylation. Large excess of cytochrome b5 compared to CYP2C8 in recombinant systems and HLMs inhibited metabolic clearance, diminishing the difference in k(cat) between the two enzymes, and may provide an explanation for the discrepancy to in vivo data. In silico studies illustrate the genetic differences between wild type and variant on the molecular level. (C) 2011 Elsevier Inc. All rights reserved.