- THIENOPYRIDINE DERIVATIVES CONTAINING UNSATURATED ALIPHATIC OLEFINIC BOND, PREPARATION METHOD AND USE THEREOF
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The present invention provides a compound having a structure of formula (I), a preparation method and use thereof, and a pharmaceutical composition containing the compound, wherein R is methyl, ethyl, propyl, vinyl or propenyl. The present invention also
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Paragraph 0131-0133
(2020/12/04)
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- In Vitro Assessment of Potential for CYP-Inhibition-Based Drug–Drug Interaction Between Vonoprazan and Clopidogrel
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Background and Objectives: It was recently proposed that CYP-mediated drug–drug interactions (DDIs) of vonoprazan with clopidogrel and prasugrel can attenuate the antiplatelet actions of the latter two drugs. Clopidogrel is metabolized to the pharmacologically active metabolite H4 and its isomers by multiple CYPs, including CYP2C19 and CYP3A4. Therefore, to investigate the possibility of CYP-based DDIs, in vitro metabolic inhibition studies using CYP probe substrates or radiolabeled clopidogrel and human liver microsomes (HLMs) were conducted in this work. Methods: Reversible inhibition studies focusing on the effects of vonoprazan on CYP marker activities and the formation of the [14C]clopidogrel metabolite H4 were conducted with and without pre-incubation using HLMs. Time-dependent inhibition (TDI) kinetics were also measured. Results: It was found that vonoprazan is not a significant direct inhibitor of any CYP isoforms (IC50 ≥ 16?μM), but shows the potential for TDI of CYP2B6, CYP2C19, and CYP3A4/5. This TDI was weaker than the inhibition induced by the corresponding reference inhibitors ticlopidine, esomeprazole, and verapamil, based on the measured potencies (kinact/KI ratio and the R2 value). In a more direct in vitro experiment, vonoprazan levels of up to 10?μM (a 100-fold higher concentration than the plasma Cmax of 75.9?nM after taking 20?mg once daily for 7?days) did not suppress the formation of the active metabolite H4 or other oxidative metabolites of [14C]clopidogrel in a reversible or time-dependent manner. Additionally, an assessment of clinical trials and post-marketing data suggested no evidence of a DDI between vonoprazan and clopidogrel. Conclusions: The body of evidence shows that the pharmacodynamic DDI reported between vonoprazan and clopidogrel is unlikely to be caused by the inhibition of CYP2B6, CYP2C19, or CYP3A4/5 by vonoprazan.
- Nishihara, Mitsuhiro,Yamasaki, Hitomi,Czerniak, Richard,Jenkins, Helen
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p. 217 - 227
(2018/11/10)
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- Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development
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Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed. (Chemical Equation Presented).
- Shaw, Scott A.,Balasubramanian, Balu,Bonacorsi, Samuel,Cortes, Janet Caceres,Cao, Kevin,Chen, Bang-Chi,Dai, Jun,Decicco, Carl,Goswami, Animesh,Guo, Zhiwei,Hanson, Ronald,Humphreys, W. Griffith,Lam, Patrick Y. S.,Li, Wenying,Mathur, Arvind,Maxwell, Brad D.,Michaudel, Quentin,Peng, Li,Pudzianowski, Andrew,Qiu, Feng,Su, Shun,Sun, Dawn,Tymiak, Adrienne A.,Vokits, Benjamin P.,Wang, Bei,Wexler, Ruth,Wu, Dauh-Rurng,Zhang, Yingru,Zhao, Rulin,Baran, Phil S.
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p. 7019 - 7032
(2015/07/27)
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- Bioactivation of Clopidogrel and Prasugrel: Factors Determining the Stereochemistry of the Thiol Metabolite Double Bond
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The antithrombotics of the tetrahydrothienopyridine series, clopidogrel and prasugrel, are prodrugs that must be metabolized in two steps to become pharmacologically active. The first step is the formation of a thiolactone metabolite. The second step is a further oxidation with the formation of a thiolactone sulfoxide whose hydrolytic opening leads to a sulfenic acid that is eventually reduced into the corresponding active cis thiol. Very few data were available on the formation of the isomer of the active cis thiol having a trans configuration of the double bond, the most striking result in that regard being that both cis and trans thiols were formed upon the metabolism of clopidogrel by human liver microsomes in the presence of glutathione (GSH), whereas only the cis thiol was detected in the sera of patients treated with this drug. This article shows that trans thiols are also formed upon the microsomal 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 to be responsible for trans thiol formation. Addition of human liver cytosol to the microsomal incubations led to a dramatic decrease of the formation of the trans thiol metabolites. These data suggest that cytosolic esterases would accelerate the hydrolytic opening of thiolactone sulfoxide intermediates and disfavor the formation of thioesters resulting from the reaction of these intermediates with GSH that is responsible for trans isomer formation. This would explain why trans thiols have not been detected in the sera of patients treated with clopidogrel.
- Dansette, Patrick M.,Levent, Dan,Hessani, Assia,Mansuy, Daniel
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p. 1338 - 1345
(2015/06/25)
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- OPTICALLY ACTIVE 2-HYDROXY TETRAHYDROTHIENOPYRIDINE DERIVATIVES, PREPARATION METHOD AND USE IN MANUFACTURE OF MEDICAMENT THEREOF
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Optically active 2-hydroxytetrahydrothienopyridine derivatives represented by Formula I and pharmaceutically acceptable salts, preparation method and use in the manufacture of a medicament thereof are disclosed. The pharmacodynamic experiment results show that the present compounds of Formula I are useful for inhibiting platelet aggregation. The pharmacokinetic experiment results show that the present compound of Formula I can be converted in vivo into pharmacologically active metabolites and are therefore useful for inhibiting platelet aggregation. Therefore, the present compounds are useful for the manufacture of a medicament for preventing or treating thrombosis and embolism related diseases.
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Paragraph 0092; 0093
(2013/07/05)
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- METHODS FOR THE TREATMENT OR PROPHYLAXIS OF THROMBOSIS OR EMBOLISM
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The present invention provides a method of ameliorating the drawbacks of anti-platelet drug named clopidogrel. The method of the resent invention comprises administration of an (S)-oxo-clopidogrel or its derivative of the Formula IIA in its free or pharma
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Page/Page column 20
(2012/03/26)
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- Overcoming clopidogrel resistance: Discovery of vicagrel as a highly potent and orally bioavailable antiplatelet agent
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A series of optically active 2-hydroxytetrahydrothienopyridine derivatives were designed and synthesized as prodrugs of clopidogrel thiolactone in order to overcome clopidogrel resistance. The final compounds were evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats. Compound 9a was selected for further in vitro and in vivo metabolism studies, since its potency was comparable to that of prasugrel and was much higher than that of clopidogrel. Preliminary pharmacokinetic study results showed that the bioavailability of clopidogrel thiolactone generated from 9a was 6-fold higher than that generated from clopidogrel, implying a much lower clinically effective dose for 9a in comparison with clopidogrel. In summary, 9a (vicagrel) holds great promise as a more potent and a safer antiplatelet agent that might have the following advantages over clopidogrel: (1) no drug resistance for CYP2C19 poor metabolizers; (2) lower dose-related toxicity due to a much lower effective dose; (3) faster onset of action.
- Shan, Jiaqi,Zhang, Boyu,Zhu, Yaoqiu,Jiao, Bo,Zheng, Weiyi,Qi, Xiaowei,Gong, Yanchun,Yuan, Fang,Lv, Fusheng,Sun, Hongbin
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experimental part
p. 3342 - 3352
(2012/06/04)
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- OPTICALLY ACTIVE 2-HYDROXY TETRAHYDROTHIENOPYRIDINE DERIVATIVES, PREPARATION METHOD AND USE IN MANUFACTURE OF MEDICAMENT THEREOF
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Optically active 2-hydroxytetrahydrothienopyridine derivatives represented by Formula I and pharmaceutically acceptable salts, preparation method and use in the manufacture of a medicament thereof are disclosed. The pharmacodynamic experiment results show that the present compounds of Formula I are useful for inhibiting platelet aggregation. The pharmacokinetic experiment results show that the present compound of Formula I can be converted in vivo into pharmacologically active metabolites and are therefore useful for inhibiting platelet aggregation. Therefore, the present compounds are useful for the manufacture of a medicament for preventing or treating thrombosis and embolism related diseases.
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Page/Page column 7-8
(2013/02/27)
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- Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite
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The aim of the current study is to identify the human cytochrome P450 (P450) isoforms involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. In the in vitro experiments using cDNA-expressed huma
- Kazui, Miho,Nishiya, Yumi,Ishizuka, Tomoko,Hagihara, Katsunobu,Farid, Nagy A.,Okazaki, Osamu,Ikeda, Toshihiko,Kurihara, Atsushi
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experimental part
p. 92 - 99
(2010/11/17)
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