(S)-2-(2-chlorophenyl)-2-(3-(2-methoxy-2-oxoethyl)-4-methylmercapto-5,6-dihydropyridine-1(2H)-yl)acetic acid | 1351983-68-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-2-(2-chlorophenyl)-2-(3-(2-methoxy-2-oxoethyl)-4-methylmercapto-5,6-dihydropyridine-1(2H)-yl)acetic acid
• 英文别名: Clopidogrel endo thiol metabolite；2-[1-[(1S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-4-sulfanyl-3,6-dihydro-2H-pyridin-5-yl]acetic acid
• CAS: 1351983-68-0
• 化学式: C₁₆H₁₈ClNO₄S
• 分子量: 355.842
• InChiKey: CXPJTQJWJQRBOF-HNNXBMFYSA-N

物化性质

• 沸点：
  513.9±50.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.92
• 重原子数：
  23.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  66.84
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  (S)-2-(2-chlorophenyl)-2-(3-(2-methoxy-2-oxoethyl)-4-methylmercapto-5,6-dihydropyridine-1(2H)-yl)acetic acid 在 三光气 、 三乙胺 、 三苯基膦 作用下， 以 氯仿 为溶剂， 以65.8%的产率得到bis-methyl-(S)-2-(1-(1-(2-chlorophenyl)-2-carboxyethyl)-4-mercapto-1,2,5,6-tetrahydropyridin-3-yl)acetate
  参考文献：
  名称：

  不饱和环胺二硫衍生物、其制备方法及医药用途

  摘要：

  本发明涉及药物化学领域，具体涉及一系列不饱和环胺二硫衍生物，这些化合物与氯吡格雷相比，具有更优的代谢特征，能够绕过人体内P450系统，具备很好的成药性。本发明还公开了上述化合物的制备方法及其在医药领域尤其是心脑血管血栓或栓塞性疾病药物领域的用途。

  公开号：

  CN111362864A
• 作为产物：
  描述：

  氯吡格雷 在 paraoxonase-1 、 cytochrome P₄₅₀ 作用下， 生成 (S)-2-(2-chlorophenyl)-2-(3-(2-methoxy-2-oxoethyl)-4-methylmercapto-5,6-dihydropyridine-1(2H)-yl)acetic acid
  参考文献：
  名称：

  氯吡格雷和普拉格雷的生物激活：硫醇代谢物双键立体化学的决定因素。

  摘要：

  四氢噻吩并吡啶系列的抗血栓药氯吡格雷和普拉格雷是前药，必须在两个步骤中代谢才能具有药理活性。第一步是形成硫代内酯代谢物。第二步是进一步氧化，形成硫代内酯亚砜，其水解开口导致亚磺酸，亚磺酸最终被还原成相应的活性顺式硫醇。关于具有双键反式构型的活性顺式硫醇异构体的形成的数据很少，在这方面最引人注目的结果是顺式和反式都在存在谷胱甘肽（GSH）的情况下，人肝微粒体在氯吡格雷的代谢中形成了硫醇，而用该药物治疗的患者血清中仅检测到顺式硫醇。该文章表明，在存在GSH的情况下，普拉格雷或其硫代内酯代谢物的微粒体代谢也会形成反式硫醇，并且只有在存在硫醇的情况下进行微粒体温育时，才会形成具有双键反式构型的代谢物。如GSH，N-乙酰半胱氨酸和巯基乙醇。由GSH与硫代内酯亚砜代谢产物反应形成的硫酯的中间形成似乎是造成反式的原因硫醇的形成。在微粒体温育中添加人肝细胞溶质导致反式硫醇代谢物形成的急剧减少。这些数据表明

  DOI：

  10.1021/acs.chemrestox.5b00133

文献信息

• 不饱和环胺半胱氨酸二硫衍生物制备方法及其医药用途
  申请人：北京沃邦医药科技有限公司

  公开号：CN112851570A

  公开（公告）日：2021-05-28

  本发明涉及药物化学领域，具体涉及一系列不饱和环胺半胱氨酸二硫衍生物，本发明还公开了上述化合物的制备方法及其医药用途。尤其用于治疗动脉粥样硬化疾病、心肌梗死、中风、外周动脉疾病、急性冠脉综合征和抗血管形成手术期间的血栓形成。
• Cytochromes P450 Catalyze Both Steps of the Major Pathway of Clopidogrel Bioactivation, whereas Paraoxonase Catalyzes the Formation of a Minor Thiol Metabolite Isomer
  作者：Patrick M. Dansette、Julien Rosi、Gildas Bertho、Daniel Mansuy

  DOI：10.1021/tx2004085

  日期：2012.2.20

  The mechanism generally admitted for the bioactivation of the antithrombotic prodrug clopidogrel, is its two-step enzymatic conversion into a biologically active thiol metabolite. The first step is a classical cytochrome P450 (P450)-dependent monooxygenation of its thiophene ring leading to 2-oxo-clopidogrel, a thiolactone metabolite. The second step was described as a P450-dependent oxidative opening of the thiolactone ring of 2-oxo-clopidogrel, with intermediate formation of a reactive sulfenic acid metabolite that is eventually reduced to the corresponding thiol 4b. A very recent paper published in Nat. Med. (Bouman et al., (2011) 17, 110) reported that the second step of clopidogrel bioactivation was not catalyzed by P450 enzymes but by paraoxonase-1(PON-1) and that PON-1 was a major determinant of clopidogrel efficacy. The results described in the present article show that there are two metabolic pathways for the opening of the thiolactone ring of 2-oxo-clopidogrel. The major one, that was previously described, results from a P450-dependent redox bioactivation of 2-oxo-clopidogrel and leads to 4b cis, two previously reported thiol diastereomers bearing an exocyclic double bond. The second, minor one, results from a hydrolysis of 2-oxo-clopidogrel, which seems to be dependent on PON-1, and leads to an isomer of 4b cis, 4b "endo", in which the double bond has migrated from an exocyclic to an endocyclic position in the piperidine ring. These results were obtained from a detailed study of the metabolism of 2-oxo-clopidogrel by human liver microsomes and human sera and analysis by HPLC-MS under conditions allowing a complete separation of the thiol metabolite isomers, either as such or after derivatization with 3'-methoxy phenacyl bromide or N-ethyl maleimide (NEM). These results also show that the major bioactive thiol isomer found in the plasma of clopidogrel-treated patients derives from 2-oxo-clopidogrel by the P450-dependent pathway. Finally, chemical experiments on 2-oxo-clopidogrel showed that this thiolactone is in equilibrium with its tautomer having a double bond inside the piperidine ring and that nucleophiles such as CH3O- preferentially react on the thioester function of this tautomer. This allowed us to understand why 4b cis has to be formed via an oxidative opening of 2-oxo-clopidogrel thiolactone, whereas a hydrolytic opening of this thiolactone ring leads to the "endo" thiol isomer 4b "endo".
• Bioactivation of Clopidogrel and Prasugrel: Factors Determining the Stereochemistry of the Thiol Metabolite Double Bond
  作者：Patrick M. Dansette、Dan Levent、Assia Hessani、Daniel Mansuy

  DOI：10.1021/acs.chemrestox.5b00133

  日期：2015.6.15

  metabolism of prasugrel or its thiolactone metabolite in the presence of GSH and that metabolites having the trans configuration of the double bond are only formed when microsomal incubations are done in the presence of thiols, such as GSH, N-acetyl-cysteine, and mercaptoethanol. Intermediate formation of thioesters resulting from the reaction of GSH with the thiolactone sulfoxide metabolite appears

  四氢噻吩并吡啶系列的抗血栓药氯吡格雷和普拉格雷是前药，必须在两个步骤中代谢才能具有药理活性。第一步是形成硫代内酯代谢物。第二步是进一步氧化，形成硫代内酯亚砜，其水解开口导致亚磺酸，亚磺酸最终被还原成相应的活性顺式硫醇。关于具有双键反式构型的活性顺式硫醇异构体的形成的数据很少，在这方面最引人注目的结果是顺式和反式都在存在谷胱甘肽（GSH）的情况下，人肝微粒体在氯吡格雷的代谢中形成了硫醇，而用该药物治疗的患者血清中仅检测到顺式硫醇。该文章表明，在存在GSH的情况下，普拉格雷或其硫代内酯代谢物的微粒体代谢也会形成反式硫醇，并且只有在存在硫醇的情况下进行微粒体温育时，才会形成具有双键反式构型的代谢物。如GSH，N-乙酰半胱氨酸和巯基乙醇。由GSH与硫代内酯亚砜代谢产物反应形成的硫酯的中间形成似乎是造成反式的原因硫醇的形成。在微粒体温育中添加人肝细胞溶质导致反式硫醇代谢物形成的急剧减少。这些数据表明
• 不饱和环胺二硫衍生物、其制备方法及医药用途
  申请人：北京翼方生物科技有限责任公司

  公开号：CN111362864A

  公开（公告）日：2020-07-03

  本发明涉及药物化学领域，具体涉及一系列不饱和环胺二硫衍生物，这些化合物与氯吡格雷相比，具有更优的代谢特征，能够绕过人体内P450系统，具备很好的成药性。本发明还公开了上述化合物的制备方法及其在医药领域尤其是心脑血管血栓或栓塞性疾病药物领域的用途。