RESUMEN
S-(+)-Methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate, also known as (S)-clopidogrel, is marketed under the trade names Plavix and Iscover. It is a potent thienopyridine-class of antithrombotic and antiplatelet drug (antiaggregant). Among the two available stereoisomers of clopidogrel, for pharmaceutical activities only the S-enantiomer is applicable, as no antithrombotic activity is observed in the R-enantiomer and causes political upheavals and social turmoil in animal experiments. Worldwide sales of Plavix amounted to $6.4 billion yearly, which ranks second. Attributed to the increased demand of (S)-clopidogrel drug, it provoked the synthetic community to devise facile synthetic approaches. This review aims to summarize the synthetic methods of (S)-clopidogrel drug reported in the literature. The present review discusses the pros and cons of each synthetic methodology, which would be beneficial to the scientific community for further developments in the synthetic methodologies for (S)-clopidogrel. In addition, the compilation approach of literature-reported synthetic strategies of (S)-clopidogrel in one platform is advantageous, supportive, and crucial for the synthetic community to elect the best synthetic methodology of (S)-clopidogrel and to create new synthesis ideas.
Asunto(s)
Técnicas de Química Sintética/métodos , Fibrinolíticos/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Ticlopidina/análogos & derivados , Animales , Clopidogrel , Descubrimiento de Drogas , Fibrinolíticos/química , Fibrinolíticos/farmacología , Humanos , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Estereoisomerismo , Ticlopidina/síntesis química , Ticlopidina/química , Ticlopidina/farmacologíaRESUMEN
Myocardial infarction, i.e., heart attack, is a fatal condition which is on the increase all over the world. It is reported that a large number of heart attack occur in morning hours which are attributable to platelet aggregation. Chronotherapy at this stage can be crucial. Clopidogrel bisulfate (CLB) is an antiplatelet agent and has become a drug of choice for prevention of heart attack. It is soluble in acidic pH and has a narrow absorption window. So, its long residence time in stomach is desirable. Therefore, a novel high density tablet was developed comprising multiparticulate pellets with pulsatile release necessary to maintain chronotherapy of heart attack. The pellets were prepared by extrusion-spheronization and coated in fluidized bed processor with different coating material to achieve pulsatile release. The size, shape of pellets, and drug release were evaluated. High density tablet containing coated pellets was formulated and evaluated for retention in stomach. Quality by design tools was used to design and optimize the processes. Timed release observed by dissolution study showed lag time of 6 h followed by burst release of drug up to 94% in 1 h. Density of tablets was found to be 2.2 g cm-3 which is more than gastric fluid. In vivo x-ray studies in rabbit revealed 8 h of gastric retention of tablet at the bottom of the stomach. Thus, CLB high density pulsatile system looks to open up a window of opportunity for developing formulations with drugs that are stable in gastric region and needed chronotheraupetic activity.
Asunto(s)
Diseño de Fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/metabolismo , Estómago/efectos de los fármacos , Ticlopidina/análogos & derivados , Animales , Clopidogrel , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/metabolismo , Liberación de Fármacos , Excipientes , Absorción Gástrica/efectos de los fármacos , Absorción Gástrica/fisiología , Mucosa Gástrica/metabolismo , Masculino , Inhibidores de Agregación Plaquetaria/síntesis química , Conejos , Solubilidad , Estómago/diagnóstico por imagen , Comprimidos , Ticlopidina/administración & dosificación , Ticlopidina/síntesis química , Ticlopidina/metabolismoRESUMEN
In the search for prodrug analogs of clopidogrel with improved metabolic characteristics and antiplatelet bioactivity, a group of clopidogrel and vicagrel analogs selectively deuterated at the benzylic methyl ester group were synthesized, characterized, and evaluated. The compounds included clopidogrel-d3 (8), 2-oxoclopidogrel-d3 (9), vicagrel-d3 (10a), and 12 vicagrel-d3 analogs (10b-10m) with different alkyl groups in the thiophene ester moiety. The D3C-O bond length in 10a was shown by X-ray single crystal diffraction to be shorter than the H3C-O bond length in clopidogrel, consistent with the slower rate of hydrolysis of 8 than of clopidogrel in rat whole blood in vitro. A study of the ability of the compounds to inhibit ADP-induced platelet aggregation in fresh rat whole blood collected 2 h after oral dosing of rats with the compounds (7.8 µmol/kg) showed that deuteration increased the activity of clopidogrel and that increasing the size of the alkyl group in the thiophene ester moiety reduced activity. A preliminary pharmacokinetic study comparing 10a with vicagrel administered simultaneously as single oral doses (72 µmol/kg of each drug) to male Wistar rats showed 10a generated more of its active metabolite than vicagrel. These results suggest that 10a is a potentially superior antiplatelet agent with improved metabolic characteristics and bioactivity, and less dose-related toxicity.
Asunto(s)
Inhibidores de Agregación Plaquetaria/metabolismo , Inhibidores de Agregación Plaquetaria/farmacocinética , Ticlopidina/análogos & derivados , Adenosina Difosfato/metabolismo , Adenosina Difosfato/farmacología , Animales , Clopidogrel , Hidrólisis , Masculino , Redes y Vías Metabólicas , Modelos Moleculares , Conformación Molecular , Fenilacetatos/síntesis química , Fenilacetatos/química , Fenilacetatos/metabolismo , Fenilacetatos/farmacología , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Ratas , Tiofenos/síntesis química , Tiofenos/química , Tiofenos/metabolismo , Tiofenos/farmacología , Ticlopidina/síntesis química , Ticlopidina/química , Ticlopidina/metabolismo , Ticlopidina/farmacocinéticaRESUMEN
Antiplatelet drugs are the cornerstone of therapy in many cardiovascular conditions. With the current success and increased use of transcatheter aortic valve implantation (TAVI), the use of antiplatelet therapy is considered part of the medical therapy for these patients. Clinicians caring for these patients need to have a thorough understanding of the pharmacology, pharmacokinetics, pharmacodynamic, and clinical efficacy and safety of commonly used antiplatelet therapy. While aspirin therapy is widely used, dual antiplatelet therapy with clopidogrel has become part of standard of care. Despite the extensive experience with clopidogrel, there are limitations such as drug interactions, metabolism genetic polymorphisms, and variability in the antiplatelet response. More predictable and more potent antiplatelet agents, prasugrel and ticagrelor, have demonstrated superior reductions in ischemic endpoints as part of dual antiplatelet therapy compared to clopidogrel, but at the cost of more major bleeding in patients with an acute coronary syndrome. Significant research needs to be conducted in the setting of TAVI to help define the optimal antiplatelet regimen.
Asunto(s)
Adenosina/análogos & derivados , Aspirina/uso terapéutico , Enfermedades Cardiovasculares/terapia , Inhibidores de Agregación Plaquetaria/uso terapéutico , Clorhidrato de Prasugrel/uso terapéutico , Ticlopidina/análogos & derivados , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Adenosina/síntesis química , Adenosina/química , Adenosina/uso terapéutico , Aspirina/síntesis química , Aspirina/química , Clopidogrel , Humanos , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Clorhidrato de Prasugrel/síntesis química , Clorhidrato de Prasugrel/química , Ticagrelor , Ticlopidina/síntesis química , Ticlopidina/química , Ticlopidina/uso terapéuticoRESUMEN
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.
Asunto(s)
Microsomas Hepáticos/metabolismo , Piperidinas/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/metabolismo , Profármacos/síntesis química , Ticlopidina/análogos & derivados , Fenómenos Biológicos , Clopidogrel , Humanos , Microsomas Hepáticos/efectos de los fármacos , Piperidinas/química , Inhibidores de Agregación Plaquetaria/química , Profármacos/química , Estereoisomerismo , Ticlopidina/síntesis química , Ticlopidina/química , Ticlopidina/metabolismoRESUMEN
To support the development of a reactive metabolite strategy, the preparation of several radiolabelled compounds such as [(14)C] Ticlopidine was required. In this report, we describe a facile and rapid synthesis of [(14)C] Ticlopidine starting from [(14)C] carbon dioxide. The compound was radiolabelled in the 2-chloromethyl portion of the molecule with a specific activity of 53.4 mCi/mmol and with a radiochemical purity of 98.5%. Storage stability was best as the hydrochloride salt in an ethanol solution.
Asunto(s)
Radiofármacos/síntesis química , Ticlopidina/síntesis química , Radioisótopos de Carbono , Técnicas de Química Sintética , Cinética , Radioquímica , Radiofármacos/química , Ticlopidina/químicaRESUMEN
The direct α-amination of ketones, esters, and aldehydes has been accomplished via copper catalysis. In the presence of catalytic copper(II) bromide, a diverse range of carbonyl and amine substrates undergo fragment coupling to produce synthetically useful α-amino-substituted motifs. The transformation is proposed to proceed via a catalytically generated α-bromo carbonyl species; nucleophilic displacement of the bromide by the amine then delivers the α-amino carbonyl adduct while the catalyst is reconstituted. The practical value of this transformation is highlighted through one-step syntheses of two high-profile pharmaceutical agents, Plavix and amfepramone.
Asunto(s)
Aminas/química , Ticlopidina/análogos & derivados , Aldehídos/química , Bromuros/química , Catálisis , Clopidogrel , Cobre/química , Dietilpropión/síntesis química , Ésteres/química , Ticlopidina/síntesis químicaRESUMEN
A first approach for catalytic asymmetric Strecker reaction of aldehydes with a secondary amine in the presence of sodium fluoride using hydroquinine as chiral catalyst was developed. The catalytic system gave α-aminonitriles in excellent yields (up to 95%) and high enantioselectivities (er up to 94:6). The efficacy of the chiral product was successfully fulfilled in the improved synthesis of (S)-clopidogrel (an antiplatelet agent).
Asunto(s)
Aldehídos/química , Aminas/química , Inhibidores de Agregación Plaquetaria/síntesis química , Quinidina/análogos & derivados , Ticlopidina/análogos & derivados , Catálisis , Clopidogrel , Espectroscopía de Resonancia Magnética , Estructura Molecular , Quinidina/química , Fluoruro de Sodio/química , Estereoisomerismo , Ticlopidina/síntesis químicaRESUMEN
We reported previously the formation of a glutathionyl conjugate of the active metabolite (AM) of clopidogrel and the covalent modification of a cysteinyl residue of human cytochrome P450 2B6 in a reconstituted system (Mol Pharmacol 80:839-847, 2011). In this work, we extended our studies of the metabolism of clopidogrel to human liver microsomes in the presence of four reductants, namely, GSH, l-Cys, N-acetyl-l-cysteine (NAC), and ascorbic acid. Our results demonstrated that formation of the AM was greatly affected by the reductant used and the relative amounts of the AM formed were increased in the following order: NAC (17%) < l-Cys (53%) < ascorbic acid (61%) < GSH (100%). AM-thiol conjugates were observed in the presence of NAC, l-Cys, and GSH. In the case of GSH, the formation of both the AM and the glutathionyl conjugate was dependent on the GSH concentrations, with similar K(m) values of ~0.5 mM, which indicates that formation of the thiol conjugates constitutes an integral part of the bioactivation processes for clopidogrel. It was observed that the AM was slowly converted to the thiol conjugate, with a half-life of ~10 h. Addition of dithiothreitol to the reaction mixture reversed the conversion, which resulted in a decrease in AM-thiol conjugate levels and a concomitant increase in AM levels, whereas addition of NAC led to the formation of AM-NAC and a concomitant decrease in AM-GSH levels. These results not only confirm that the AM is formed through oxidative opening of the thiolactone ring but also suggest the existence of an equilibrium between the AM, the thiol conjugates, and the reductants. These factors may affect the effective concentrations of the AM in vivo.
Asunto(s)
Microsomas Hepáticos/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Ticlopidina/análogos & derivados , Clopidogrel , Relación Dosis-Respuesta a Droga , Glutatión/farmacología , Humanos , Microsomas Hepáticos/efectos de los fármacos , Oxidación-Reducción , Compuestos de Sulfhidrilo/síntesis química , Ticlopidina/síntesis química , Ticlopidina/metabolismoRESUMEN
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.
Asunto(s)
Fenilacetatos/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Profármacos/síntesis química , Tiofenos/síntesis química , Ticlopidina/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Clopidogrel , Resistencia a Medicamentos , Femenino , Técnicas In Vitro , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Fenilacetatos/química , Fenilacetatos/farmacología , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Profármacos/química , Profármacos/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Ticlopidina/síntesis química , Ticlopidina/química , Ticlopidina/farmacologíaRESUMEN
The convention of loading with clopidogrel 300 mg before coronary intervention may be due for change, but to what? Newer antiplatelet agents may offer better outcomes, at some financial cost. Disappointingly for decision-making clinicians, head-to-head comparisons for the newer alternatives are not available. We systematically review and compare the three alternative strategies: clopidogrel 600 mg, prasugrel and ticagrelor. A total of 14 studies have compared these strategies with the long-standing convention of 300 mg. Throughout this analysis, we consistently report incremental costs and consequences using clopidogrel 300 mg as the reference strategy. Risk ratios for major adverse cardiovascular events at 30 days were 0.74 (95% confidence interval 0.66-0.82, p=0.002) for clopidogrel 600 mg, 0.78 (0.69-0.89; p<0.001) for prasugrel and 0.88 (0.77-1.00; p=0.045) for ticagrelor. All-cause mortality risk ratios were 0.87 (0.74-1.03) with clopidogrel 600 mg, 0.95 (0.78-1.16) with prasugrel and 0.78 (0.69-0.89) with ticagrelor. TIMI major bleeding has risk ratio 0.92 (0.74-1.16; p=0.85) with clopidogrel 600 mg, 1.32 (1.03-1.16; p=0.03) with prasugrel and 1.25 (1.03-1.53; p=0.03) with ticagrelor. Incremental cost for the first year was £0.32 (US$0.50, 0.40) with clopidogrel 600 mg, £608 (US$977, 709) with prasugrel and £665 (US$1068, 775) with ticagrelor. All three strategies have shown a similar reduction in MACE at 30 days by comparison to clopidogrel 300 mg. All three strategies offer progressive benefit, most marked with Ticagrelor. Whether this is worth both the risk of non-compliance with twice-a-day dosing in real-life patients lacking the same motivation as their trial-volunteer counterparts, and the 2000-fold difference in incremental cost, is the remaining matter for debate.
Asunto(s)
Adenosina/análogos & derivados , Enfermedades Cardiovasculares/inducido químicamente , Hemorragia/inducido químicamente , Piperazinas/administración & dosificación , Tiofenos/administración & dosificación , Ticlopidina/análogos & derivados , Adenosina/administración & dosificación , Adenosina/efectos adversos , Animales , Enfermedades Cardiovasculares/epidemiología , Clopidogrel , Hemorragia/epidemiología , Humanos , Piperazinas/efectos adversos , Piperazinas/síntesis química , Clorhidrato de Prasugrel , Tiofenos/efectos adversos , Tiofenos/síntesis química , Ticagrelor , Ticlopidina/administración & dosificación , Ticlopidina/efectos adversos , Ticlopidina/síntesis químicaRESUMEN
A methodological study devoted to the Mannich-like multicomponent synthesis of the antiplatelet agent (±)clopidogrel (7) and the ethyl ester analogue 6 is described. The process involves the formation of 2-chlorophenyl zinc bromide (2) and its subsequent reaction with an alkyl glyoxylate and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3). We demonstrate that the organozinc reagent 2 also constitutes a very convenient nucleophile for the multicomponent synthesis of the benzylamine core of ticlopidine (9).
Asunto(s)
Bromuros/química , Ticlopidina/análogos & derivados , Ticlopidina/química , Ticlopidina/síntesis química , Compuestos de Zinc/química , Clopidogrel , Cobalto/química , Estructura Molecular , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Zinc/químicaRESUMEN
Methyl (R)-o-chloromandelate ((R)-), which is an intermediate for a platelet aggregation inhibitor named clopidogrel, was obtained in >99% ee by the asymmetric reduction of methyl o-chlorobenzoylformate (2) (up to 1.0 M) with recombinant E. coli overproducing a versatile carbonyl reductase.
Asunto(s)
Escherichia coli/metabolismo , Ácidos Mandélicos/síntesis química , Ácidos Mandélicos/metabolismo , Fenilacetatos/metabolismo , Ticlopidina/análogos & derivados , Oxidorreductasas de Alcohol/química , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , Biotransformación , Clopidogrel , Escherichia coli/enzimología , Escherichia coli/genética , Microbiología Industrial , Ácidos Mandélicos/química , Estructura Molecular , Fenilacetatos/química , Estereoisomerismo , Ticlopidina/síntesis químicaRESUMEN
We propose that anti-platelet thienopyridines, such as ticlopidine or clopidogrel, are thrombolytic owing to endothelial release of prostacyclin (PGI2) and tissue plasminogen activator (t-PA). In this study we used anaesthetised Wistar rats with extracorporal circulation in which arterial blood superfused thrombi which adhered to a strip of collagen. Weight of thrombi was continuously monitored. When administered intravenously, clopidogrel or its R enantiomer deprived of anti-platelet action, both at doses of 3 mg x kg(-1), produced lost in weight of thrombi by 14.1 +/- 1.3% or 16.0 +/- 1.4% (n = 9), and at doses 10 mg x kg(-1) by 28.3 +/- 2.3% or 30.4 +/- 1.9% (n = 8), respectively. Maximum of thrombolysis occurred 30-45 min following the drug administration. Ticlopidine at a dose of 30 mg x kg(-1) reduced weight of thrombi by 33.7 +/- 1.7% (n = 32). Thrombolytic action of ticlopidine was accompanied by a rise in 6!keto-PGF1alpha blood levels from 0.42 +/- 0.10 to 1.58 +/- 0.29 ng x ml(-1) and t-PA antigen plasma levels from 4.70 +/- 1.00 to 12.90 +/- 1.15 ng x ml(-1) (n = 7). Five out of eleven tested thienopyridine congeners with pyrimidine or pyrimidinone instead of pyridine rings had thrombolytic potencies similar to that of clopidogrel (ED30s at a range of 6.2-11.4 mg x kg(-1)). A substantial increase in thrombolytic potency (ED30s at a range of 0.3-2.1 mg x kg(-1)) was observed for congeners in which thienyl ring was condensed with an additional cyclopentyl, cyclohexyl or cycloheptyl structures or in which thienopyridine complex was replaced for a pyridopyrimidine one. We claim that thienopyridines, independently of their delayed anti-platelet action, do produce immediate thrombolysis in vivo. This new activity emulates capacity of their native, non-metabolised molecules to release prostacyclin and tissue plasminogen activator. We have also shown that structural changes in molecules of thienopyridines may intensify their thrombolytic potency.