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Bioorg Med Chem Lett ; 24(5): 1294-8, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24513044


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.

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
Bioorg Med Chem Lett ; 23(11): 3239-43, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23602442


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.

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
J Med Chem ; 56(4): 1704-14, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23368907


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.

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
J Cardiovasc Pharmacol ; 55(6): 609-16, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20224421


Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. Apixaban was evaluated in rat thrombosis and hemostasis models. Thrombosis was produced in the carotid artery by FeCl2 application, in the vena cava by either FeCl2 application or tissue factor injection, and in an arterial-venous shunt. Hemostasis was assessed using cuticle, renal cortex, and mesenteric artery bleeding times. Intravenous apixaban infusions of 0.1, 0.3, 1, and 3 mg/kg per hour increased the ex vivo prothrombin time to 1.24, 1.93, 2.75, and 3.98 times control, respectively. The 0.3, 1, and 3-mg/kg per hour doses inhibited thrombosis in all models. Concentrations for 50% thrombus reduction ranged from 1.84 to 7.57 microM. The 3-mg/kg per hour dose increased cuticle, renal, and mesenteric bleeding times to 1.92, 2.13, and 2.98 times control, respectively. Lower doses had variable (1 mg/kg per hour) or no effect (0.1, 0.3 mg/kg per hour) on hemostasis. Heparin's prolongation of renal and cuticle bleeding time was twice that of apixaban when administered at a dose that approximated apixaban (3 mg/kg per hour) efficacy in arterial thrombosis. In summary, apixaban was effective in a broad range of thrombosis models at doses producing modest increases in multiple bleeding time models.

Antitrombina III/uso terapêutico , Trombose/tratamento farmacológico , Animais , Anticoagulantes/uso terapêutico , Tempo de Sangramento , Coagulação Sanguínea/efeitos dos fármacos , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Hemostasia/efeitos dos fármacos , Heparina/uso terapêutico , Masculino , Tempo de Protrombina , Pirazóis , Piridonas , Ratos , Ratos Sprague-Dawley , Trombose/prevenção & controle
Eur J Pharmacol ; 570(1-3): 167-74, 2007 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-17597608


The effect of inhibiting activated blood coagulation factor XIa was determined in rat models of thrombosis and hemostasis. BMS-262084 is an irreversible and selective small molecule inhibitor of factor XIa with an IC(50) of 2.8 nM against human factor XIa. BMS-262084 doubled the activated thromboplastin time in human and rat plasma at 0.14 and 2.2 microM, respectively. Consistent with factor XIa inhibition, the prothrombin time was unaffected at up to 100 microM. BMS-262084 administered as an intravenous loading plus sustaining infusion was effective against FeCl(2)-induced thrombosis in both the vena cava and carotid artery. Maximum thrombus weight reductions of 97 and 73%, respectively (P<0.05), were achieved at a pretreatment dose of 12 mg/kg+12 mg/kg/h which increased the ex vivo activated thromboplastin time to 3.0 times control. This dose level also arrested growth of venous and arterial thrombi when administered after partial thrombus formation. BMS-262084 was most potent in FeCl(2)-induced venous thrombosis, decreasing thrombus weight 38% (P<0.05) at a threshold dose of 0.2 mg/kg+0.2 mg/kg/h. In contrast, doses of up to 24 mg/kg+24 mg/kg/h had no effect on either tissue factor-induced venous thrombosis or the ex vivo prothrombin time. Doses of up to 24 mg/kg+24 mg/kg/h also did not significantly prolong bleeding time provoked by either puncture of small mesenteric blood vessels, template incision of the renal cortex, or cuticle incision. These results demonstrate that pharmacologic inhibition of factor XIa achieves antithrombotic efficacy with minimal effects on provoked bleeding.

Azetidinas/uso terapêutico , Trombose das Artérias Carótidas/tratamento farmacológico , Fator XIa/antagonistas & inibidores , Fibrinolíticos/uso terapêutico , Hemostáticos/uso terapêutico , Piperazinas/uso terapêutico , Trombose Venosa/tratamento farmacológico , Animais , Trombose das Artérias Carótidas/fisiopatologia , Humanos , Masculino , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Ratos , Ratos Sprague-Dawley , Triptases/antagonistas & inibidores , Trombose Venosa/fisiopatologia
J Pharmacol Exp Ther ; 322(1): 369-77, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17420297


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.

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