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1.
ChemMedChem ; 9(10): 2327-43, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24989964

RESUMO

Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y1 antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.


Assuntos
Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ureia/análogos & derivados , Animais , Humanos , Espectroscopia de Ressonância Magnética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Espectrometria de Massas por Ionização por Electrospray , Ureia/farmacocinética , Ureia/farmacologia
2.
J Med Chem ; 57(14): 6150-64, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-24931384

RESUMO

Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y12 and P2Y1. Blocking P2Y12 receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y1 antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y12 inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y1 antagonist, 1. This paper describes further optimization of 1 by introducing 4-aryl groups at the hydroxylindoline in two series. In the neutral series, 10q was identified with excellent potency and desirable pharmacokinetic (PK) profile. It also demonstrated similar antithrombotic efficacy with less bleeding compared with the known P2Y12 antagonist prasugrel in rabbit efficacy/bleeding models. In the basic series, 20c (BMS-884775) was discovered with an improved PK and liability profile over 1. These results support P2Y1 antagonism as a promising new antiplatelet target.


Assuntos
Descoberta de Drogas , Indóis/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y1/metabolismo , Animais , Coagulação Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indóis/química , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/química , Antagonistas do Receptor Purinérgico P2Y/síntese química , Antagonistas do Receptor Purinérgico P2Y/química , Coelhos , Ratos , Relação Estrutura-Atividade , Trombose/tratamento farmacológico
3.
Bioorg Med Chem Lett ; 24(11): 2481-5, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24767843

RESUMO

Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5 µM with 10 µM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3.


Assuntos
Indóis/química , Piperidinas/química , Receptores Purinérgicos P2Y1/metabolismo , Tiadiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Indóis/administração & dosagem , Estrutura Molecular , Piperidinas/administração & dosagem , Ratos , Relação Estrutura-Atividade , Tiadiazóis/administração & dosagem , Tiadiazóis/química
4.
J Immunol ; 192(9): 4083-92, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24670803

RESUMO

CD40-CD40L interactions play a critical role in regulating immune responses. Blockade of CD40L by Abs, such as the anti-CD40L Ab 5c8, demonstrated positive clinical effects in patients with autoimmune diseases; however, incidents of thromboembolism (TE) precluded further development of these molecules. In this study, we examined the role of the Fc domain interaction with FcγRs in modulating platelet activation and potential for TE. Our results show that the interaction of the 5c8 wild-type IgG1 Fc domain with FcγRs is responsible for platelet activation, as measured by induction of PAC-1 and CD62P. A version of 5c8 with a mutated IgG1 tail was identified that showed minimal FcγR binding and platelet activation while maintaining full binding to CD40L. To address whether Fc effector function is required for immunosuppression, a potent Ab fragment, termed a "domain Ab" (dAb), against murine CD40L was identified and fused to a murine IgG1 Fc domain containing a D265A mutation that lacks Fc effector function. In vitro, this dAb-Fc demonstrated comparable potency to the benchmark mAb MR-1 in inhibiting B cell and dendritic cell activation. Furthermore, the anti-CD40L dAb-Fc exhibited a notable efficacy comparable to MR-1 in various preclinical models, such as keyhole limpet hemocyanin-induced Ab responses, alloantigen-induced T cell proliferation, "heart-to-ear" transplantation, and NZB × NZW F1 spontaneous lupus. Thus, our data show that immunosuppression and TE can be uncoupled and that a CD40L dAb with an inert Fc tail is expected to be efficacious for treating autoimmune diseases, with reduced risk for TE.


Assuntos
Doenças Autoimunes/imunologia , Ligante de CD40/imunologia , Ativação Plaquetária/efeitos dos fármacos , Anticorpos de Domínio Único/farmacologia , Animais , Anticorpos Monoclonais/efeitos adversos , Modelos Animais de Doenças , Células HEK293 , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Ativação Plaquetária/imunologia , Receptores de IgG/imunologia , Anticorpos de Domínio Único/imunologia , Ressonância de Plasmônio de Superfície , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Transfecção
5.
Bioorg Med Chem Lett ; 24(5): 1294-8, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24513044

RESUMO

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.


Assuntos
Compostos de Fenilureia/química , Inibidores da Agregação de Plaquetas/química , Antagonistas do Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Tiazóis/química , Ureia/análogos & derivados , Administração Oral , Animais , Cães , Meia-Vida , Macaca fascicularis , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Trombose/tratamento farmacológico , Ureia/farmacocinética , Ureia/farmacologia , Ureia/uso terapêutico
6.
Bioorg Med Chem Lett ; 23(24): 6825-8, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24269480

RESUMO

A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional activities, as well as improved aqueous solubility. Among them, the piperidine 4a showed the best overall profile with favorable PK parameters.


Assuntos
Aminas/química , Agonistas do Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Ureia/análogos & derivados , Difosfato de Adenosina/farmacologia , Aminas/síntese química , Aminas/farmacocinética , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Piperidinas/química , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacocinética , Ligação Proteica , Agonistas do Receptor Purinérgico P2Y/síntese química , Agonistas do Receptor Purinérgico P2Y/farmacocinética , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacocinética
7.
J Med Chem ; 56(22): 9275-95, 2013 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-24164581

RESUMO

Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.


Assuntos
Desenho de Drogas , Conformação Molecular , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Receptores Purinérgicos P2Y1/metabolismo , Compostos de Espiro/farmacologia , Compostos de Espiro/farmacocinética , Ureia/farmacologia , Ureia/farmacocinética , Animais , Disponibilidade Biológica , Humanos , Indóis/química , Modelos Moleculares , Compostos de Fenilureia/química , Compostos de Fenilureia/metabolismo , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y1/química , Homologia de Sequência de Aminoácidos , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Ureia/química , Ureia/metabolismo
9.
Bioorg Med Chem Lett ; 23(12): 3519-22, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23668989

RESUMO

Five-membered-ring heterocyclic urea mimics have been found to be potent and selective antagonists of the P2Y1 receptor. SAR of the various heterocyclic replacements is presented, as well as side-chain SAR of the more potent thiadiazole ring system which leads to thiadiazole 4c as a new antiplatelet agent.


Assuntos
Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y1/química , Tiadiazóis/química , Tiadiazóis/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Humanos , Cinética , Ligação Proteica , Relação Estrutura-Atividade , Ureia/química
10.
Bioorg Med Chem Lett ; 23(11): 3239-43, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23602442

RESUMO

Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.


Assuntos
Fibrinolíticos/química , Compostos de Fenilureia/química , Antagonistas do Receptor Purinérgico P2Y/química , Piridinas/química , Receptores Purinérgicos P2Y1/química , Ureia/química , Animais , Células CACO-2 , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fibrinolíticos/síntese química , Fibrinolíticos/farmacocinética , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Tempo de Tromboplastina Parcial , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Coelhos , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Solubilidade , Relação Estrutura-Atividade , Trombose/tratamento farmacológico , Ureia/farmacocinética , Ureia/uso terapêutico , Água/química
11.
J Med Chem ; 56(4): 1704-14, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23368907

RESUMO

Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 ± 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile.


Assuntos
Fibrinolíticos/síntese química , Compostos de Fenilureia/síntese química , Antagonistas do Receptor Purinérgico P2Y/síntese química , Piridinas/síntese química , Ureia/análogos & derivados , Animais , Arteriopatias Oclusivas/sangue , Arteriopatias Oclusivas/tratamento farmacológico , Tempo de Sangramento , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Células HEK293 , Humanos , Masculino , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Trombose/sangue , Trombose/tratamento farmacológico , Ureia/síntese química , Ureia/química , Ureia/farmacologia
12.
Thromb Haemost ; 101(1): 108-15, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19132196

RESUMO

The new P2Y(12) antagonist prasugrel produces greater inhibition of ADP-induced platelet aggregation (IPA) and reduction of thrombotic events in patients versus approved doses of clopidogrel, but increases major bleeding. We examined whether IPA level or P2Y(12) receptor occupancy (RO) could be optimized to better balance the efficacy and bleeding effects of these thienopyridines and reduce the response variability in rabbits. Rabbits were given three daily oral doses of clopidogrel (0.3-30 mg/kg/d), prasugrel (0.03-10 mg/kg/d) or vehicle (n = 6-40/group). Electrically-induced carotid artery thrombosis (AT, % thrombus weight reduction), cuticle bleeding time (BT, fold-increase over control), IPA to 20 microM ADP (% inhibition of peak light transmission) and RO (% inhibition of [(33)P]-2MeS-ADP binding to P2Y(1)-blocked platelets) were determined 2-3 hours after the last dose. ED(50) (doses for half-maximal effect, mg/kg/d) of AT, BT, IPA and RO were 1.6, 6.7, 1.9 and 1.4 for clopidogrel vs. 1.2, 1.9, 0.5 and 0.2 for prasugrel. IPA of 30-40% for both compounds produced the optimal balances of efficacy (AT: 50-60%) and BT of about 2-fold with significant RO of 70-80%. IPA of 50-60% achieved higher efficacy (AT: 60-80%), but with increased BT of five- to six-fold and >90% RO. Box-plot suggests no significant difference in the IPA and RO response variability between both compounds. Clopidogrel was 1.3-7 times less potent than prasugrel in rabbits, depending upon which biomarker was studied. The ratio of efficacy: bleeding was most favorable at a moderate IPA of 30% to 40%. Both compounds had similar IPA and RO response variability.


Assuntos
Fibrinolíticos/farmacologia , Hemostasia/efeitos dos fármacos , Piperazinas/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tiofenos/farmacologia , Trombose/tratamento farmacológico , Ticlopidina/análogos & derivados , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/metabolismo , Administração Oral , Animais , Ligação Competitiva , Tempo de Sangramento , Clopidogrel , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrinolíticos/administração & dosagem , Fibrinolíticos/metabolismo , Fibrinolíticos/toxicidade , Hemorragia/induzido quimicamente , Masculino , Piperazinas/administração & dosagem , Piperazinas/metabolismo , Piperazinas/toxicidade , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/metabolismo , Inibidores da Agregação de Plaquetas/toxicidade , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2 , Coelhos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Tionucleotídeos/metabolismo , Tiofenos/administração & dosagem , Tiofenos/metabolismo , Tiofenos/toxicidade , Trombose/sangue , Ticlopidina/administração & dosagem , Ticlopidina/metabolismo , Ticlopidina/farmacologia , Ticlopidina/toxicidade
13.
J Cardiovasc Pharmacol ; 49(5): 316-24, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17513951

RESUMO

Target levels of ex vivo inhibition of platelet aggregation (IPA) induced by adenosine diphosphate (ADP) that produce clinically relevant effects of clopidogrel, a P2Y12 antagonist, are unclear. We examined standard and modified IPA and P2Y12 receptor occupancy as predictors of antithrombotic (% thrombus weight reduction) and bleeding time (BT, fold-increase over control) effects of clopidogrel in rabbit models of carotid artery thrombosis and cuticle bleeding, respectively. Standard and modified IPA with 20 microM ADP were measured in the absence and presence of partial P2Y1 blockade, respectively. Clopidogrel maximally produced standard IPA of 57% +/- 5%, antithrombotic effect of 85% +/- 1%, BT increase of 6.0 +/- 0.4-fold and P2Y12 receptor occupancy of 87% +/- 5%. Surprisingly, a clopidogrel dose that produced a low standard IPA of 17% +/- 4% and P2Y12 receptor occupancy of 39% +/- 5% achieved a significant antithrombotic activity of 55% +/- 2% with a moderate increase in BT of 2.0 +/- 0.1-fold. This underestimation of clopidogrel efficacy by standard IPA was improved by measuring either modified IPA or P2Y12 receptor occupancy. These results suggest that in clopidogrel-treated rabbits, low standard IPA is associated with significant antithrombotic effects. Moreover, modified IPA and P2Y12 receptor occupancy appear to better predict the magnitude of clopidogrel's efficacy compared with standard IPA, which may be a better predictor of BT.


Assuntos
Plaquetas/metabolismo , Trombose das Artérias Carótidas/prevenção & controle , Trombose das Artérias Carótidas/fisiopatologia , Artéria Carótida Primitiva/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Receptores Purinérgicos P2/metabolismo , Ticlopidina/análogos & derivados , Difosfato de Adenosina/metabolismo , Difosfato de Adenosina/farmacologia , Análise de Variância , Animais , Aspirina/farmacologia , Biomarcadores/sangue , Tempo de Sangramento , Plaquetas/efeitos dos fármacos , Trombose das Artérias Carótidas/sangue , Artéria Carótida Primitiva/fisiopatologia , Clopidogrel , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hemostasia/efeitos dos fármacos , Masculino , Valor Preditivo dos Testes , Ligação Proteica/efeitos dos fármacos , Coelhos , Receptores Purinérgicos P2/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Tromboxano B2/sangue , Ticlopidina/farmacologia
14.
J Pharmacol Exp Ther ; 322(1): 369-77, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17420297

RESUMO

We determined the dose response of the ADP antagonist clopidogrel (0.3-50 mg/kg p.o.) in rat models of thrombosis and provoked bleeding and correlated these activities to ex vivo platelet activation. Carotid artery thrombosis was induced by FeCl(2). Bleeding time was measured by mesenteric vessel puncture and renal cortex or cuticle incision. Platelet biomarkers included standard ADP-induced aggregation, P2Y(12) receptor occupancy, and phosphorylation of vasodilator-stimulated phosphoprotein. Clopidogrel decreased thrombus weight up to 78%, caused maximal prolongation of cuticle and mesenteric bleeding, but had little effect on renal bleeds. Due to the steep mesenteric dose response, further comparisons concentrated on cuticle bleeding. The half-maximal inhibitory dose (ED(50)) for thrombus reduction was 2.4 +/- 0.4 mg/kg, with 10 mg/kg providing optimal blood flow preservation and thrombus reduction. The ED(50) for bleeding was 10.5 +/- 3.4 mg/kg. Increased bleeding was intermediate (3-fold) at 10 mg/kg and maximal (6-fold) at 30 mg/kg. All biomarkers were affected, but with differing sensitivity. ED(50)s for peak platelet aggregation to 10 microM ADP (11.9 +/- 0.4 mg/kg) and the vasodilator-stimulated phosphoprotein index (16.4 +/- 1.3 mg/kg) approximated the higher ED(50) for bleeding. ED(50)s for ligand binding (3.0 +/- 0.3 mg/kg) and late aggregation (5.1 +/- 0.4 mg/kg) better matched the lower ED(50) for antithrombotic activity. Aspirin exerted lesser effects on bleeding (42-70% increase in all models) and thrombosis (24% inhibition). In summary, antithrombotic doses of clopidogrel have limited effects on bleeding and standard measures of platelet aggregation. Other biomarkers may be more sensitive for tracking antithrombotic efficacy.


Assuntos
Fibrinolíticos/farmacologia , Hemostáticos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Ticlopidina/análogos & derivados , Difosfato de Adenosina/farmacologia , Animais , Aspirina/farmacologia , Biomarcadores , Moléculas de Adesão Celular/metabolismo , Clopidogrel , Relação Dose-Resposta a Droga , Masculino , Proteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2/metabolismo , Ticlopidina/farmacologia
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