767612-34-0Relevant academic research and scientific papers
Preparation method and medical application of unsaturated cyclic amine pyridine disulfide derivative
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, (2021/05/19)
The invention relates to the field of medicinal chemistry, in particular to a series of unsaturated cyclic amine pyridine disulfide derivatives, and further discloses a preparation method and medical application of the compounds. The invention discloses a novel unsaturated cyclic amine pyridine disulfide derivative and a preparation method and application thereof for the first time, especially for treating atherosclerotic diseases, myocardial infarction, stroke, peripheral arterial diseases, acute coronary syndromes and thrombosis in an anti-angiogenesis operation period.
Chemical Synthesis of Clopidogrel Active Metabolites and Disulfide Conjugate Prodrugs
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Paragraph 0059; 0061, (2021/04/02)
A method of synthesizing a clopidogrel metabolite is provided. A piperidone intermediate is formed from a mandelate. An asymmetric ketone reduction of the piperidone intermediate is performed. A mercapto installation is performed on the piperidone intermediate to form a clopidogrel metabolite that includes a 4-carbon chiral center having an (R) configuration.
STABLE COMPOSITIONS OF (7AS,2'S)-2-OXOCLOPIDOGREL AND ITS PHARMACEUTICAL SALTS
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Page/Page column 14, (2021/04/17)
The present invention discloses stable oral pharmaceutical composition containing therapeutically effective amount of (7aS,2'S)-2-oxoclopidogrel and/or its salts or derivatives, in combination with pharmaceutically acceptable adjuvants or carriers. More particularly, the present invention discloses highly pure (7aS,2'S)-2-oxoclopidogrel and/or its salts, processes for manufacturing pure and stable (7aS,2'S)-2-oxoclopidogrel and stable compositions having a shelf-life of at least one year or more.
Clopidogrel metabolic active body disulfide derivativeS as well as preparation method and medical application thereof
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, (2020/08/18)
The invention relates to the field of medicinal chemistry, and provides a series of clopidogrel metabolic active body disulfide derivatives, pharmaceutically acceptable salts or solvates. Compared with clopidogrel, the compounds have better metabolic characteristics, can bypass a P450 system in a human body, and have good druggability. The invention also discloses a preparation method of the compounds and application of the compounds in the field of medicines, especially in the field of medicines for treating cardiovascular and cerebrovascular thrombosis or embolic diseases.
Bioactivation of Clopidogrel and Prasugrel: Factors Determining the Stereochemistry of the Thiol Metabolite Double Bond
Dansette, Patrick M.,Levent, Dan,Hessani, Assia,Mansuy, Daniel
, p. 1338 - 1345 (2015/06/25)
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.
MIXED DISULFIDE CONJUGATES OF THIENOPYRIDINE COMPOUNDS AND USES THEREOF
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Page/Page column 38; 42-43, (2014/07/23)
This invention is in the field of medicinal chemistry. In particular, the invention relates to mixed disulfide conjugates of thienopyridine compounds, and their use as therapeutics for the treatment, amelioration, and prevention of cardiovascular diseases
Formation, reactivity, and antiplatelet activity of mixed disulfide conjugates of clopidogrel
Zhang, Haoming,Lauver, D. Adam,Lucchesi, Benedict R.,Hollenberg, Paul F.
, p. 848 - 856 (2013/05/22)
In this work, we investigated the formation, reactivity, and antiplatelet activity of various mixed disulfide conjugates of clopidogrel. Our results showed that the production of the active metabolite (AM) from 2-oxoclopidogrel by human liver microsomes (HLMs) is greatly affected by the thiol reductants used. Among the 10 thiol compounds tested, glutathione (GSH) is most efficient in producing the AM at a rate of 167 pmoles AM/ min/mg HLM. Interestingly, no AM but only the mixed disulfide conjugates were formed in the presence of 6-chloropyridazine- 3-thiol (CPT), 2,5-dimethylfuran-3-thiol, and 3-nitropyridine-2- thiol (NPT). The mass spectrometry (MS) and MS2 spectra of the conjugates of these thiol compounds confirmed the presence of a mixed disulfide bond linkage between the AM and the thiol reductants. Kinetic studies revealed that the mixed disulfide conjugates were capable of exchanging thiols with GSH to release the AM with second order rate constants ranging from 1.2 to 28 M21s21. The mixed disulfide conjugates of CPT and NPT showed potent inhibition of platelet aggregation after pretreatment with 1 mM GSH, confirming that the AM is responsible for the antiplatelet activity of clopidogrel. Collectively, our results provide strong support for a cytochrome P450 (P450)-mediated bioactivation mechanism involving the initial formation of a glutathionyl conjugate, followed by thiol-disulfide exchange with another GSH molecule to release the AM. Furthermore, the stable mixed disulfide conjugates identified in this study provide a platform to quantitatively generate the therapeutic AM without the need for P450- mediated bioactivation. This property can be further explored to overcome the interindividual variability in clopidogrel therapy. Copyright
COMPOSITIONS AND METHODS FOR THE TREATMENT OF ATHEROTHROMBOSIS
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, (2013/03/26)
The disclosures herein provide compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, enantiomers, stereoisomers, solvates, and hydrates thereof. These salts may be formulated as pharmaceutical compositions. The pharmaceutical compositions may be formulated for peroral administration- transdermal administration, transmucosal, syrups, topical, extended release, sustained release, or injection. Such compositions may foe used to treatment of vascular disorders or conditions such as thrombotic cerebrovascular or cardiovascular disease or its associated complications.
Cytochromes P450 catalyze both steps of the major pathway of clopidogrel bioactivation, whereas paraoxonase catalyzes the formation of a minor thiol metabolite isomer
Dansette, Patrick M.,Rosi, Julien,Bertho, Gildas,Mansuy, Daniel
experimental part, p. 348 - 356 (2012/06/30)
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 monooxygena
Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite
Kazui, Miho,Nishiya, Yumi,Ishizuka, Tomoko,Hagihara, Katsunobu,Farid, Nagy A.,Okazaki, Osamu,Ikeda, Toshihiko,Kurihara, Atsushi
experimental part, p. 92 - 99 (2010/11/17)
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
