阿地溴胺杂质10 | 1708930-15-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 奎宁环
• 中文名称: 阿地溴胺杂质10
• 英文名称: (3R)-3-hydroxy-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide
• 英文别名: LAS34823；3(R)-hydroxy-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane bromide；LAS-34823 bromide；(3R)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-3-ol;bromide
• CAS: 1708930-15-7
• 化学式: Br*C₁₆H₂₄NO₂
• 分子量: 342.276
• InChiKey: OVZUMPBMNBEYDM-FPSFNUPFSA-M

物化性质

• 熔点：
  181 - 185°C
• 溶解度：
  DMF（轻微，超声处理）、DMSO（轻微）、甲醇（轻微）

计算性质

• 辛醇/水分配系数(LogP)：
  -0.94
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  29.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  阿地溴胺杂质10 在 glucose-6-phosphate dehydrogenase 、 glucose-6-phosphate 、 human recombinant cytochrome P₄₅₀ CYP₂D₆ 、 烟酰胺腺嘌呤双核苷酸磷酸盐 作用下， 生成 LAS188638
  参考文献：
  名称：

  In vitro liver metabolism of aclidinium bromide in preclinical animal species and humans: Identification of the human enzymes involved in its oxidative metabolism

  摘要：

  The metabolism of aclidinium bromide, a novel long-acting antimuscarinic drug for the maintenance treatment of chronic obstructive pulmonary disorder, has been investigated in liver microsomes and hepatocytes of mice, rats, rabbits, dogs, and humans. Due to the rapid hydrolysis of this ester compound, two distinct radiolabeled forms of aclidinium were studied. The main biotransformation route of aclidinium was the hydrolytic cleavage of the ester moiety, resulting in the formation of the alcohol metabolite (M2. LAS34823) and carboxylic acid metabolite (m3, LAS34850), which mainly occurred nonenzymatically. By comparison, the oxidative metabolism was substantially lower and the metabolite profiles were similar across all five species examined. Aclidinium was metabolized oxidatively to four minor primary metabolites that were identified as monohydroxylated derivatives of aclidinium at the phenyl (M4) and glycolyl (m6 and m7) moieties of the molecule. The NADPH-dependent metabolite m4 involved the loss of one of the thiophene rings of aclidinium. Incubations with human recombinant P450 isoforms and inhibition studies with selective chemical inhibitors and antibodies of human P450 enzymes demonstrated that the oxidative metabolism of aclidinium is primarily mediated by CYP3A4 and CYP2D6. Additionally, up to eight secondary metabolites were also characterized, involving further hydrolysis, oxidation, or glucuronidation of the primary metabolites. Also, the liver oxidative metabolism of the alcohol metabolite (LAS34823) resulted in the production of one hydroxylated metabolite (M1) mediated by human CYP2D6, whereas the acid metabolite (LAS34850) was not metabolized enzymatically, although a minor non-enzymatic and NADPH-dependent reduction was observed. (C) 2010 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2010.12.013
• 作为产物：
  描述：

  阿地溴铵 在 human recombinant cytochrome P₄₅₀ 、 还原型辅酶II(NADPH)四钠盐 作用下， 生成 2-羟基-2,2-双(2-噻吩)乙酸 、 阿地溴胺杂质10
  参考文献：
  名称：

  Identification of the Human Enzymes Responsible for the Enzymatic Hydrolysis of Aclidinium Bromide

  摘要：

  Aclidinium bromide [LAS34273, 3 R -(2-hydroxy-2,2-dithiophen-2-yl-acetoxy)-1-(3-phenoxy-propyl)1-azonia bicycle-[2.2.2]-octane bromide]是一种用于治疗慢性阻塞性肺病的新型长效吸入性毒蕈碱拮抗剂，在人体和动物血浆中显示出快速水解。这一过程既有非酶解（k h, 0.0075 min-1），也有酶解。本研究的目的是调查阿利地尼铵在人体中的体外酶水解作用。通过使用选择性对氧磷酶、芳基酯酶、羧基酯酶、乙酰胆碱酯酶和丁酰胆碱酯酶化学抑制剂对人血浆进行抑制研究，以及使用纯人胆碱酯酶进行孵育，确定人丁酰胆碱酯酶是负责酶水解阿西地铵的最重要酯酶。此外，人类细胞色素 P450 和人类血清白蛋白都没有参与阿利丁胺的酶酯裂解。人肺中的丁酰胆碱酯酶活性低于人血浆中的丁酰胆碱酯酶活性。研究表明，阿克利定能竞争性地抑制人类丁酰胆碱酯酶（K i，2.7 μM）和乙酰胆碱酯酶（6.3 μM），但对其他人类酯酶及其水解代谢产物的活性没有任何影响。这些结果表明，在低于 1 nM 的临床相关血浆中，涉及人胆碱酯酶的临床相互作用的可能性很小。

  DOI：

  10.1124/dmd.109.031724

文献信息

• [EN] PROCESS FOR THE PREPARATION OF ACLIDINIUM BROMIDE<br/>[FR] PROCÉDÉ POUR LA PRÉPARATION DE BROMURE D'ACLIDINIUM
  申请人：GLENMARK PHARMACEUTICALS LTD ; GLENMARK GENERICS LTD

  公开号：WO2015071824A1

  公开（公告）日：2015-05-21

  The present invention relates to process for the preparation of aclidiunium or intermediates thereof. More particularly, it relates to the preparation of aclidinium bromide.

  本发明涉及一种制备aclidiunium或其中间体的方法。更具体地说，涉及制备aclidinium溴化物的方法。
• Aclidinium bromide, a new, long-acting, inhaled muscarinic antagonist: In vitro plasma inactivation and pharmacological activity of its main metabolites
  作者：Sonia Sentellas、Israel Ramos、Joan Albertí、Miquel Salvà、Francisca Antón、Montserrat Miralpeix、Jorge Beleta、Amadeu Gavaldà

  DOI：10.1016/j.ejps.2010.01.004

  日期：2010.3

  Aclidinium bromide is a novel, long-acting inhaled muscarinic antagonist drug in Phase III clinical trials for chronic obstructive pulmonary disease (COPD). The aims of this study were to evaluate the in vitro stability of the ester drug aclidinium in plasma from various species, and the in vitro and in vivo pharmacological activity of its hydrolysis metabolites. Following incubation of aclidinium in pooled samples of human, rat, guinea pig or dog plasma, the rate of hydrolysis was quantified by reversed phase ultra performance liquid chromatography and mass spectrometry. Tiotropium and ipratropium were used as comparators. The in vitro biochemical profile of the hydrolysis metabolites of aclidinium was assessed in human M-1 to M-5 muscarinic receptors and in a standard selectivity panel (85 G protein-coupled receptors [GPCRs], ion channels and enzymes). The bronchodilator activity of the metabolites of aclidinium bromide was studied in guinea pigs after acetylcholine-induced bronchoconstriction.Aclidinium was rapidly hydrolysed into carboxylic acid and alcohol derivatives in guinea pig, rat, human and dog plasma with half-lives of 38, 11.7, 2.4 and 1.8 min, respectively. In contrast, >70% of tiotropium and ipratropium remained unchanged in the plasma after 60 min of incubation. The carboxylic acid and alcohol metabolites had no significant affinity for any of the muscarinic receptors, other GPCRs, ion channels or enzymes studied and showed no relevant antibronchoconstrictory activity in vivo. These results suggest that aclidinium may have a reduced systemic exposure and therefore less propensity for class-related systemic side effects in the clinical setting. (C) 2010 Elsevier B.V. All rights reserved.