RESUMO
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
Assuntos
Amidas/química , Complemento C1s/antagonistas & inibidores , Desenho de Fármacos , Polietilenoglicóis/química , Inibidores de Proteases/síntese química , Tiofenos/química , Animais , Complemento C1s/metabolismo , Meia-Vida , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , RatosRESUMO
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.
Assuntos
Complemento C1s/antagonistas & inibidores , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Animais , Sítios de Ligação , Meia-Vida , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their alpha-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.
Assuntos
Benzodiazepinas/síntese química , Proteínas Nucleares/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteína Supressora de Tumor p53/agonistas , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Técnicas de Química Combinatória , Cristalografia por Raios X , Humanos , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Proteínas Proto-Oncogênicas c-mdm2 , Estereoisomerismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/biossínteseRESUMO
We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral administration of 8 at 30 and 50 mg/kg reduced thrombus weight by 87 and 94%, respectively. In an anesthetized rat antithrombotic model, where electrical stimulation of the carotid artery created a thrombus, 8 prolonged occlusion time 2- and 3-fold at 0.1 and 1.0 mg/kg, i.v., respectively, and more than doubled activated clotting time and activated partial thromboplastin time at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully progressed through phase 1 studies.
Assuntos
Anticoagulantes/síntese química , Fibrinolíticos/síntese química , Guanidinas/síntese química , Pirazinas/síntese química , Trombina/antagonistas & inibidores , Motivos de Aminoácidos , Animais , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Células CACO-2 , Cristalografia por Raios X , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Cães , Método Duplo-Cego , Eletrocardiografia , Feminino , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacologia , Guanidinas/farmacocinética , Guanidinas/farmacologia , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Pirazinas/farmacocinética , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade , Trombina/química , Trombose Venosa/sangue , Trombose Venosa/tratamento farmacológicoRESUMO
Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.
Assuntos
Sulfonatos de Arila/síntese química , Complemento C1s/antagonistas & inibidores , Inibidores de Serina Proteinase/síntese química , Amidinas/síntese química , Amidinas/farmacologia , Angioedema/tratamento farmacológico , Sulfonatos de Arila/farmacologia , Fibrinolisina/farmacologia , Rejeição de Enxerto/tratamento farmacológico , Humanos , Isquemia Miocárdica/tratamento farmacológico , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Trombina/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/farmacologiaRESUMO
Activation of the classical pathway of complement has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury and acute transplant rejection. The trypsin-like serine protease C1s represents a pivotal upstream point of control in the classical pathway of complement activation and is therefore likely to be a useful target in the therapeutic intervention of these disease states. A series of thiopheneamidine-based inhibitors of C1s has been optimized to give a 70 nM inhibitor that inhibits the classical pathway of complement activation in vitro.