RESUMO
BACKGROUND: To date, the lack of potent and selective inhibitors has hampered the physiological assessment of modulation of the cardiac slowly activating delayed rectifier current, I(Ks). The present study, using the I(Ks) blocker L-768,673, represents the first in vivo assessment of the cardiac electrophysiological and antiarrhythmic effects of selective I(Ks) blockade. METHODS AND RESULTS: In an anesthetized canine model of recent (8.5+/-0.4 days) anterior myocardial infarction, 0.003 to 0.03 mg/kg L-768,673 IV significantly suppressed electrically induced ventricular tachyarrhythmias and reduced the incidence of lethal arrhythmias precipitated by acute, thrombotically induced posterolateral myocardial ischemia. Antiarrhythmic protection afforded by L-768,673 was accompanied by modest 7% to 10% increases in noninfarct zone ventricular effective refractory period, 3% to 5% increases in infarct zone ventricular effective refractory period, and 4% to 6% increases in QTc interval. In a conscious canine model of healed (3 to 4 weeks) anterior myocardial infarction, ventricular fibrillation was provoked by transient occlusion of the left circumflex coronary artery during submaximal exercise. Pretreatment with 0.03 mg/kg L-768,673 IV elicited a modest 7% increase in QTc, prevented ventricular fibrillation in 5 of 6 animals, and suppressed arrhythmias in 2 additional animals. CONCLUSIONS: The present findings suggest that selective blockade of I(Ks) may be a potentially useful intervention for the prevention of malignant ischemic ventricular arrhythmias.
Assuntos
Acetamidas/uso terapêutico , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Benzodiazepinonas/uso terapêutico , Bloqueio Cardíaco/terapia , Isquemia Miocárdica/tratamento farmacológico , Disfunção Ventricular/tratamento farmacológico , Animais , Arritmias Cardíacas/etiologia , Modelos Animais de Doenças , Cães , Eletrocardiografia , Isquemia Miocárdica/complicações , Sistema Nervoso Simpático/fisiologia , Disfunção Ventricular/etiologiaRESUMO
Regulation by the p38 mitogen-activated protein (MAP) kinase signaling pathway of monocytic inflammatory functions was evaluated using L-790,070, a potent and selective inhibitor of p38 MAP kinase. Three major functions of monocytes were investigated: differentiation, chemotaxis, and phagocytosis. L-790,070 inhibited serum-induced monocyte differentiation with an IC50 of 0.5 nM. Monocyte chemotaxis induced by RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemotactic protein- (MCP-1), and fMLP were all sensitive to L-790,070. When titrated, L-790,070 inhibited MCP-1-induced chemotaxis in a concentration-dependent manner with an IC50 of 0.3 nM. However, the ability of serum-derived macrophages to phagocytose apoptotic neutrophils was unaffected by L-790,070. The concentration with which L-790,070 inhibited both differentiation and chemotaxis was similar to that necessary to inhibit p38 MAP kinase activation of MAPKAP kinase (0.3 nM) in response to stimulation by lipopolysaccharide. Therefore, the data in this report suggest that the mechanism by which L-790,070 blocked monocyte differentiation and prevented chemotaxis was by inhibiting p38 MAP kinase activity.
Assuntos
Quimiotaxia , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/fisiologia , Adulto , Apoptose/imunologia , Diferenciação Celular , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neutrófilos/imunologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Soroalbumina Bovina/farmacologia , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.
Assuntos
Aminopiridinas/síntese química , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Proteínas Quinases Ativadas por Mitógeno , Administração Oral , Aminopiridinas/química , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Macaca mulatta , Camundongos , Ratos , Estimulação Química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Proteínas Quinases p38 Ativadas por MitógenoAssuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Antiarrítmicos/síntese química , Antiarrítmicos/farmacologia , Benzodiazepinonas/síntese química , Benzodiazepinonas/farmacologia , Coração/efeitos dos fármacos , Bloqueadores dos Canais de Potássio , Administração Oral , Animais , Células Cultivadas , Cães , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Cobaias , Coração/fisiologia , Humanos , Miocárdio/citologia , Canais de Potássio/fisiologia , XenopusRESUMO
The synthesis and biological activity of a series of 3,6-substituted quinazolinediones and quinazolinones are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of these structures as central templates for nonpeptide RGD mimics.