Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35
Filtrar
Filtros adicionais











Intervalo de ano
1.
Sci Transl Med ; 9(371)2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-28053157

RESUMO

Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care.


Assuntos
Anticorpos/uso terapêutico , Fibrinolíticos/uso terapêutico , Hemorragia/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Receptores de Trombina/antagonistas & inibidores , Administração Oral , Animais , Plaquetas/metabolismo , Cobaias , Células HEK293 , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Domínios Proteicos , Receptor PAR-1/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Trombina/química , Trombose , Resultado do Tratamento
2.
J Thromb Thrombolysis ; 40(4): 416-23, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26249722

RESUMO

BMS-654457 ((+) 3'-(6-carbamimidoyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-2-yl)-4-carbamoyl-5'-(3-methyl-butyrylamino)-biphenyl-2-carboxylic acid) is a small-molecule factor XIa (FXIa) inhibitor. We evaluated the in vitro properties of BMS-654457 and its in vivo activities in rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT). Kinetic studies conducted in vitro with a chromogenic substrate demonstrated that BMS-654457 is a reversible and competitive inhibitor for FXIa. BMS-654457 increased activated partial thromboplastin time (aPTT) without changing prothrombin time. It was equipotent in prolonging the plasma aPTT in human and rabbit, and less potent in rat and dog. It did not alter platelet aggregation to ADP, arachidonic acid and collagen. In vivo, BMS-654457 or vehicle was given IV prior to initiation of thrombosis or cuticle transection. Preservation of integrated carotid blood flow over 90 min (iCBF, % control) was used as a marker of antithrombotic efficacy. BMS-654457 at 0.37 mg/kg + 0.27 mg/kg/h produced almost 90 % preservation of iCBF compared to its vehicle (87 ± 10 and 16 ± 3 %, respectively, n = 6 per group) and increased BT by 1.2 ± 0.04-fold (P < 0.05). At a higher dose (1.1 mg/kg + 0.8 mg/kg/h), BMS-654457 increased BT by 1.33 ± 0.08-fold. This compares favorably to equivalent antithrombotic doses of reference anticoagulants (warfarin and dabigatran) and antiplatelet agents (clopidogrel and prasugrel) which produced four- to six-fold BT increases in the same model. In summary, BMS-654457 was effective in the prevention of arterial thrombosis in rabbits with limited effects on BT. This study supports inhibition of FXIa, with a small-molecule, reversible and direct inhibitor as a promising antithrombotic therapy with a wide therapeutic window.


Assuntos
Fator XIa/antagonistas & inibidores , Fibrinolíticos/farmacologia , Trombose/tratamento farmacológico , Animais , Tempo de Sangramento , Cães , Fibrinolíticos/química , Humanos , Tempo de Tromboplastina Parcial , Coelhos , Ratos , Especificidade da Espécie , Trombose/sangue
3.
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
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.
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
7.
Bioorg Med Chem Lett ; 23(18): 5239-43, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23927973

RESUMO

In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.


Assuntos
Ácidos Carboxílicos/química , Descoberta de Drogas , Fator VIIa/antagonistas & inibidores , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacologia , Benzamidinas , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Fator VIIa/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Serino Proteinase/síntese química , Relação Estrutura-Atividade
9.
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
10.
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
11.
J Thromb Thrombolysis ; 34(2): 199-207, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22588534

RESUMO

A role for platelets in the pathogenesis of venous thrombosis was suggested by clinical and preclinical studies. However, examination of the platelet receptor, P2Y1, in this area has been limited. The goal of the current study was to examine effects of P2Y1 deletion, or selective antagonism with MRS2500, in oxidative venous thrombosis in mice. The P2Y12 antagonist, clopidogrel, was included as a reference agent. Anesthetized C57BL/6 or genetically modified mice underwent 3.5 or 5 % FeCl(3)-induced vena cava thrombosis. Pharmacokinetic properties of MRS2500 were defined for dose selection. Platelet aggregation and renal or tail bleeding times (BT) were measured to put antithrombotic effects into perspective. P2Y1 deletion significantly reduced (p < 0.001) venous thrombus weight by 74 % in 3.5 % FeCl(3) injury compared to P2Y1(+/+) littermates. MRS2500 (2 mg/kg, i.v.) significantly decreased (p < 0.001) thrombus weight 64 % in C57BL/6 mice. In the more severe 5 % FeCl(3)-induced injury model, thrombus weight significantly (p < 0.001) decreased 68 % in P2Y1(-/-) mice versus P2Y1(+/+) mice, and MRS2500 (2 mg/kg) was also beneficial (54 % decrease, p < 0.01). Renal BT doubled in P2Y1(-/-) versus P2Y1(+/+) mice, and increased threefold with MRS2500 compared to vehicle. Tail BT was markedly prolonged in P2Y1(-/-) mice (7.9X) and in C57BL/6 mice given MRS2500. The current study demonstrates that P2Y1 deletion or antagonism significantly reduced venous thrombosis in mice, suggesting that P2Y1 receptors play a role in the pathogenesis of venous thrombosis, at least in this species. However as with many antithrombotic agents the benefit comes at the potential price of an increase in provoked bleeding times.


Assuntos
Nucleotídeos de Desoxiadenina/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Receptores Purinérgicos P2Y1/metabolismo , Veias Cavas , Trombose Venosa/tratamento farmacológico , Animais , Plaquetas/metabolismo , Cloretos/efeitos adversos , Cloretos/farmacologia , Compostos Férricos/efeitos adversos , Compostos Férricos/farmacologia , Deleção de Genes , Camundongos , Camundongos Knockout , Noxas/efeitos adversos , Noxas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/genética , Receptores Purinérgicos P2Y1/genética , Trombose Venosa/induzido quimicamente , Trombose Venosa/genética
12.
Thromb Haemost ; 107(6): 1141-50, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22398951

RESUMO

Plasma kallikrein is a multifunctional serine protease involved in contact activation of coagulation. Deficiency in humans is characterised by prolonged activated partial thromboplastin time (aPTT); however, the balance between thrombosis and haemostasis is not fully understood. A study of plasma kallikrein-deficient mice revealed increased aPTT, without prolonged bleeding time. Prekallikrein antisense oligonucleotide (ASO) treatment in mice suggested potential for a positive therapeutic index. The current goal was to further define the role of plasma kallikrein in coagulation. Blood pressure and heart rate were normal in plasma kallikrein-deficient mice, and mice were completely protected from occlusion (100 ± 1.3% control flow) in 3.5% FeCl3 -induced arterial thrombosis versus heterozygotes (20 ± 11.4%) and wild-type littermates (8 ± 0%). Vessels occluded in 8/8 wild-type, 7/8 heterozygotes, and 0/8 knockouts. Anti-thrombotic protection was less pronounced in 5% FeCl3-induced arterial injury. Integrated blood flow was 8 ± 0% control in wild-type and heterozygotes, and significantly (p<0.01) improved to 43 ± 14.2% in knockouts. The number of vessels occluded was similar in all genotypes. Thrombus weight was significantly reduced in knockouts (-47%) and heterozygotes (-23%) versus wild-type in oxidative venous thrombosis. Average tail bleeding time increased modestly in knockout mice compared to wild-type. Average renal bleeding times were similar in all genotypes. These studies confirm and extend studies with prekallikrein ASO, and demonstrate that plasma kallikrein deletion prevents occlusive thrombus formation in mice with a minimal role in provoked bleeding. Additional support for the significance of the intrinsic pathway in the coagulation cascade is provided, as well as for a potential new anti-thrombotic approach.


Assuntos
Hemostasia , Calicreína Plasmática/metabolismo , Pré-Calicreína/metabolismo , Trombose/prevenção & controle , Animais , Tempo de Sangramento , Cloretos , Modelos Animais de Doenças , Compostos Férricos , Hemorragia/sangue , Hemorragia/genética , Hemostasia/genética , Heterozigoto , Camundongos , Camundongos Knockout , Oligonucleotídeos Antissenso/metabolismo , Tempo de Tromboplastina Parcial , Fenótipo , Calicreína Plasmática/genética , Pré-Calicreína/genética , Trombose/sangue , Trombose/induzido quimicamente , Trombose/genética , Fatores de Tempo , Trombose Venosa/sangue , Trombose Venosa/induzido quimicamente , Trombose Venosa/genética , Trombose Venosa/prevenção & controle
13.
Bioorg Med Chem Lett ; 21(24): 7516-21, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22041058

RESUMO

The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.7 µM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide-valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.


Assuntos
Anticoagulantes/química , Inibidores do Fator Xa , Piperidonas/química , Inibidores de Serino Proteinase/química , Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Fator Xa/metabolismo , Humanos , Lactamas/química , Conformação Molecular , Piperidonas/síntese química , Piperidonas/farmacologia , Estrutura Terciária de Proteína , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade
14.
J Thromb Thrombolysis ; 32(2): 129-37, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21614454

RESUMO

BMS-262084 is a 4-carboxy-2-azetidinone-containing irreversible inhibitor of FXIa, which is selective over other coagulation proteases. We evaluated the in vitro and in vivo properties of BMS-262084 in rabbits. Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrolytic-mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. BMS-262084 was infused IV from 1 h before thrombus induction or cuticle transection to the end of the experiment. In vitro, BMS-262084 prolonged activated partial thromboplastin time (aPTT) with EC(2x) (concentration required to double aPTT) of 10.6 µM in rabbit plasma, and did not prolong prothrombin time (PT), thrombin time (TT) and HepTest. In vivo, BMS-262084 produced dose-dependent antithrombotic effects in rabbits with antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT of 0.4, 0.7 and 1.5 mg/kg/h IV, respectively. BMS-262084 increased ex vivo aPTT dose-dependently without changes in PT and TT. The antithrombotic effect of BMS-262084 was significantly correlated with its ex vivo aPTT, supporting the use of ex vivo aPTT as a pharmacodynamic biomarker. BMS-262084 did not alter ex vivo rabbit platelet aggregation to ADP and collagen. BT (fold-increase) determined at 3 and 10 mg/kg/h of BMS-262084 were 1.17 ± 0.04 and 1.52 ± 0.07*, respectively (*P < 0.05 vs. control). This study demonstrated that BMS-262084 prevented experimental thrombosis at doses with low BT effects in rabbits, and suggests that a small molecule FXIa inhibitor may represent a promising antithrombotic therapy.


Assuntos
Azetidinas/farmacologia , Fator XIa/antagonistas & inibidores , Fibrinolíticos/farmacologia , Piperazinas/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Trombose Venosa/tratamento farmacológico , Animais , Azetidinas/efeitos adversos , Tempo de Sangramento , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fibrinolíticos/efeitos adversos , Masculino , Piperazinas/efeitos adversos , Testes de Função Plaquetária/métodos , Coelhos , Trombose Venosa/sangue
15.
Thromb Res ; 127(6): 560-4, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21396684

RESUMO

INTRODUCTION: Published evidence suggests that phosphoinositide 3 kinase-ß (PI3K-ß) plays an important role in platelet aggregation and shear activation. TGX-221 is a selective PI3K-ß inhibitor with a good separation of anti-thrombotic efficacy and bleeding (therapeutic index) in rats. Our goal was to further evaluate potential of a PI3K-ß inhibitor as an anti-thrombotic agent by determining the therapeutic index in another species and efficacy model. Reported effects of TGX-221 in rats were also confirmed. MATERIALS AND METHODS: TGX-221 (0.3 + 0.3, 1 + 1, 3 + 3 mg/kg + mg/kg/hr, i.v.) or vehicle was given to mice starting 15 min prior to FeCl(3) arterial thrombosis (AT), tail or kidney bleeding time (BT) procedures. RESULTS: Integrated blood flow over 30 min (%baseline mean ± SEM) improved (p < 0.05) with TGX-221 doses 1 + 1 (49 ± 13.9%) and 3+3 (88 ± 10.6%) versus 0.3 + 0.3 (10 ± 0.8%) and vehicle (10 ± 0.6%). Vascular patency (non-occluded/total arteries) improved (p < 0.01) with TGX-221 doses of 3 + 3 (7/8), but not 0.3 + 0.3 (0/8) or 1 + 1 (4/8) versus vehicle (0/8). Tail BT (sec) increased (p < 0.05) with TGX-221 doses of 3 + 3 (median 1560) and 1 + 1 (1305) versus vehicle (225). Mean renal BT (sec) increased (p < 0.05) in all TGX-221 groups (3 + 3: 510 + 26; 1 + 1: 478 + 41; 0.3 + 0.3: 246 + 37) versus vehicle (123 + 9). For comparison, a reference agent, aspirin (30 mpk, i.p.) increased tail BT 1.9X and renal BT 2.6X. CONCLUSIONS: The novel finding of a clear impact on hemostasis by TGX-221 was demonstrated by increased bleeding in two models in mice at anti-thrombotic doses. The results suggest a narrower therapeutic index for this PI3K-ß inhibitor than previously recognized, at least for this species.


Assuntos
Plaquetas/efeitos dos fármacos , Fibrinolíticos/farmacologia , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Pirimidinonas/farmacologia , Animais , Tempo de Sangramento , Trombose das Artérias Carótidas/sangue , Trombose das Artérias Carótidas/tratamento farmacológico , Trombose das Artérias Carótidas/enzimologia , Modelos Animais de Doenças , Fibrinolíticos/sangue , Fibrinolíticos/toxicidade , Hemorragia/induzido quimicamente , Humanos , Rim/irrigação sanguínea , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/sangue , Morfolinas/toxicidade , Fosfatidilinositol 3-Quinases/sangue , Pirimidinonas/sangue , Pirimidinonas/toxicidade , Ratos , Ratos Sprague-Dawley , Cauda/irrigação sanguínea
16.
J Cardiovasc Pharmacol ; 55(6): 609-16, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20224421

RESUMO

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.


Assuntos
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
17.
Arterioscler Thromb Vasc Biol ; 30(3): 388-92, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20139363

RESUMO

The dose-limiting issue with available anticoagulant therapies is bleeding. Is there an approach that could provide antithrombotic protection with reduced bleeding? One hypothesis is that targeting proteases upstream from the common pathway provides a reduction in thrombin sufficient to impede occlusive thrombosis yet allows enough thrombin generation to support hemostasis. The impairment of intrinsic coagulation by selective inhibition of factor XI (FXI) leaves the extrinsic and common pathways of coagulation intact, making FXI a drug target. This concept is supported by the observation that human deficiency in FXI results in a mild bleeding disorder compared with other coagulation factor deficiencies, and that elevated levels of FXI are a risk factor for thromboembolic disease. Moreover, FXI knockout mice have reduced thrombosis with little effect on hemostasis. The results from genetic models have been supported by studies using neutralizing antibodies, peptide inhibitors, and small-molecule inhibitors. These agents impede thrombosis without affecting bleeding time in a variety of experimental animals, including primates. Together, these data strongly support FXIa inhibition as a viable method to increase the ratio of benefit to risk in an antithrombotic drug.


Assuntos
Anticoagulantes/uso terapêutico , Fator XIa/antagonistas & inibidores , Trombose Venosa/tratamento farmacológico , Animais , Anticoagulantes/efeitos adversos , Coagulação Sanguínea/fisiologia , Modelos Animais de Doenças , Fator XIa/genética , Fator XIa/fisiologia , Hemorragia/etiologia , Hemorragia/fisiopatologia , Hemostasia/fisiologia , Humanos , Camundongos , Camundongos Knockout , Medição de Risco , Trombose Venosa/prevenção & controle
18.
Bioorg Med Chem Lett ; 19(24): 6882-9, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19896847

RESUMO

We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.


Assuntos
Anticoagulantes/química , Inibidores do Fator Xa , Guanidinas/química , Inibidores de Serino Proteinase/química , Anticoagulantes/farmacologia , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Descoberta de Drogas , Guanidinas/farmacologia , Humanos , Concentração Inibidora 50 , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 19(15): 4034-41, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19541481

RESUMO

The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.


Assuntos
Antitrombina III/farmacologia , Benzofuranos/farmacologia , Guanidinas/química , Lactamas/química , Administração Oral , Animais , Antitrombina III/química , Benzofuranos/química , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Cães , Haplorrinos , Humanos , Concentração Inibidora 50 , Cinética , Lactamas/farmacologia , Ligantes , Modelos Químicos , Ratos , Relação Estrutura-Atividade , Tioureia/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA