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Usage

Uses

Used in Cardiovascular Applications:
PRASUGREL METABOLITE R-138727 is used as an antiplatelet agent for the prevention of thrombotic events, such as myocardial infarction, stroke, and peripheral arterial disease, in patients with atherosclerosis or history of such events. It works by irreversibly binding to the P2Y12 receptor on platelets, inhibiting ADP-stimulated platelet activation and aggregation, and reducing thrombo-inflammatory markers.
Used in Research and Development:
PRASUGREL METABOLITE R-138727 is used as a research tool for studying the mechanisms of platelet activation and aggregation, as well as the effects of other blood cells, calcium, and aspirin on these processes. This helps in understanding the role of platelets in thrombosis and the development of new antiplatelet therapies.
Used in Drug Interaction Studies:
PRASUGREL METABOLITE R-138727 is used in drug interaction studies to evaluate the potential effects of other medications on the pharmacokinetics and pharmacodynamics of Prasugrel. This is important for identifying potential drug-drug interactions and optimizing the safety and efficacy of combination therapies.
Used in Quality Control and Standardization:
PRASUGREL METABOLITE R-138727 is used as a reference compound for the quality control and standardization of Prasugrel formulations. This ensures the consistency, purity, and potency of the drug, as well as its metabolites, in various pharmaceutical products.

Upstream product

• 1234572-11-2 C₁₈H₂₀FNO₄S 
• 150322-43-3 prasugel 
• 150322-38-6 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one 
• 70-18-8 GLUTATHIONE 
• 1234572-10-1 R-133490 

Downstream Products

• 1234699-44-5 C₂₇H₂₈FNO₅S 

Relevant academic research and scientific papers

A high-purity prasugrel preparation method

A high-purity prasugrel preparation method, compared with the prior art, the invention adopts the new preparation process, by acylation and esterification, condensation, dehydrohalogenation, hydrolysis, cyclization and acetylation can be for preparing high-purity prasugrel, mild conditions, yield is higher; at the same time 1 - alkenyl - [six hydrogen pyrazoles - 1 - (α - cyclopropyl carbonyl - 2 - fluorobenzyl) - 2 - yl] - acetic acid R ester alkali is added to the catalyst so that the hydrolysis reaction can be carried through to the end, further improves the reaction yield, in addition to the 2 - acetoxy - 5 - (α - cyclopropyl carbonyl - 2 - fluorobenzyl) - 4, 5, 6, 7 - tetrahydro-thieno [3, 2 - c] pyridine has further purification, to obtain a high purity prasugrel, and the unexpected technical effects.

Bioactivation of Clopidogrel and Prasugrel: Factors Determining the Stereochemistry of the Thiol Metabolite Double Bond

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.

Metabolic activation of prasugrel: Nature of the two competitive pathways resulting in the opening of its thiophene ring

The mechanism generally admitted for the bioactivation of the antithrombotic prodrug, prasugrel, 1c, is its two-step enzymatic conversion into a biologically active thiol metabolite. The first step is an esterase-catalyzed hydrolysis of its acetate function leading to a thiolactone metabolite 2c. The second step was described as a cytochrome P450 (P450)-dependent oxidative opening of the thiolactone ring of 2c, with intermediate formation of a reactive sulfenic acid metabolite that is eventually reduced to the corresponding active thiol 3c. This article describes a detailed study of the metabolism of 1c by human liver microsomes and human sera, with an analysis by HPLC-MS under conditions allowing a complete separation of the thiol metabolite isomers, after derivatization with 3′-methoxy phenacyl bromide. It shows that there are two competing metabolic pathways for the opening of the 2c thiolactone ring. The major one, which was previously described, results from a P450- and NADPH-dependent redox bioactivation of 2c and leads to 3c, two previously reported thiol diastereomers bearing an exocyclic double bond. It occurs with NADPH-supplemented human liver microsomes but not with human sera. The second one results from a hydrolysis of 2c and leads to an isomer of 3c, 3c endo, in which the double bond has migrated from an exocyclic to an endocyclic position in the piperidine ring. It occurs both with human liver microsomes and human sera, and does not require NADPH. However, it requires Ca2+ and is inhibited by paraoxon, which suggests that it is catalyzed by a thioesterase such as PON-1. Chemical experiments have confirmed that hydrolytic opening of thiolactone 2c exclusively leads to derivatives of the endo thiol isomer 3c endo.

Biotransformation of prasugrel, a novel thienopyridine antiplatelet agent, to the pharmacologically active metabolite

Prasugrel, a novel thienopyridine antiplatelet agent, undergoes rapid hydrolysis in vivo to a thiolactone, R-95913, which is further converted to its thiol-containing, pharmacologically active metabolite, R-138727, by oxidation via cytochromes P450 (P450). We trapped a sulfenic acid metabolite as a mixed disulfide with 2-nitro-5-thiobenzoic acid in an incubation mixture containing the thiolactone R-95913, expressed CYP3A4, and NADPH. Further experiments investigated one possible mechanism for the conversion of the sulfenic acid to the active thiol metabolite in vitro. A mixed disulfide form of R-138727 with glutathione was found to be a possible precursor of R-138727 in vitro when glutathione was present. The rate constant for the reduction of the glutathione conjugate of R-138727 to R-138727 was increased by addition of human liver cytosol to the human liver microsomes. Thus, one possible mechanism for the ultimate formation of R-138727 in vitro can be through formation of a sulfenic acid mediated by P450s followed possibly by a glutathione conjugation to a mixed disulfide and reduction of the disulfide to the active metabolite R-138727. Copyright

Cyclic amino compounds

A cyclic amino compound represented by the following formula: or a pharmacologically acceptable salt thereof. R1is a substitutable phenyl group. R2is a substitutable aliphatic acyl group, a substitutable benzoyl group or an alkoxycar

Cyclic amine derivatives

A cyclic amine derivative represented by the following formula: wherein R1 represents a substituted or unsubstituted phenyl group, R2 represents a substituted of unsubstituted C1-C8 aliphatic acyl group, a substituted or unsubstituted benzoyl group or a C1-C4 alkoxycarbonyl group, and R3 represents a substituted 3 to 7 membered saturated cyclic amino group which may form a fused ring; or pharmaceutically acceptable salts thereof. The compounds and salts have excellent platelet aggregation inhibitory action. They are useful for the treatment and prevention of such diseases as embolism, thrombosis or arteriosclerosis and for the preparation of pharmaceutical compositions for such uses.