RESUMEN
Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.
Asunto(s)
Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Descubrimiento de Drogas/métodos , Inhibidores del Factor Xa , Piridinas/síntesis química , Piridinas/farmacología , Administración Oral , Animales , Anticoagulantes/administración & dosificación , Benzamidas/administración & dosificación , Dominio Catalítico/efectos de los fármacos , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/genética , Factor Xa/metabolismo , Humanos , Macaca fascicularis , Piridinas/administración & dosificación , Conejos , RatasRESUMEN
A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant activity, but with low oral bioavailability. The 5-chloroindole and 6-chlorobenzo[b]thiophene groups are optimal as the factor Xa S1 binding elements. The strategy of incorporating a side chain on the piperazine nucleus to enhance binding affinity has been examined.
Asunto(s)
Benzamidinas/farmacología , Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/farmacología , Benzamidinas/química , Benzamidinas/farmacocinética , Disponibilidad Biológica , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacocinéticaRESUMEN
A variety of P4 motifs have been examined to increase the binding affinity and in vitro anticoagulant potency of our biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamide-based fXa inhibitors. Highly potent 2-naphthyl-P1 fXa inhibitors (K(i)< or =2 nM) with improved in vitro anticoagulant activity (2xTG< or =1 microM) and respectable pharmacokinetic properties have been discovered.
Asunto(s)
Amidas/química , Antitrombina III/química , Inhibidores del Factor Xa , Pirazoles/química , Amidas/metabolismo , Amidas/farmacología , Animales , Antitrombina III/metabolismo , Antitrombina III/farmacología , Humanos , Unión Proteica , Pirazoles/metabolismo , Pirazoles/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Using N,N-dialkylated benzamidines as the novel P4 motifs, we have designed and synthesized a class of 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent and selective fXa inhibitors with significantly improved hydrophilicity and in vitro anticoagulant activity. These benzamidine-P4 fXa inhibitors have displayed excellent oral bioavailability and long half-life.
Asunto(s)
Amidas/síntesis química , Antitrombina III/síntesis química , Benzamidinas/antagonistas & inhibidores , Pirazoles/síntesis química , Administración Oral , Amidas/administración & dosificación , Amidas/metabolismo , Animales , Antitrombina III/administración & dosificación , Antitrombina III/metabolismo , Benzamidinas/metabolismo , Disponibilidad Biológica , Diseño de Fármacos , Humanos , Pirazoles/administración & dosificación , Pirazoles/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
OBJECTIVE: In this study we test the hypothesis that blood/plasma-based prothrombinase assays, rather than inhibition of purified factor Xa (fXa), are predictive of in vivo antithrombotic activity. METHODS AND RESULTS: Six fXa inhibitors with equivalent nanomolar Ki were studied in thrombin generation assays using human plasma/blood and endogenous macromolecular substrate. In all assays, benzamidine inhibitors were more potent (100 to 800 nmol/L) than the aminoisoquinolines (5 to 58 micromol/L) or neutral inhibitors (3 to 10 micromol/L). A similar rank order of compound inhibition was also seen in purified prothrombinase assays as well as in a rabbit model of deep vein thrombosis. CONCLUSIONS: Assays using prothrombinase with protein substrates are better predictors of in vivo efficacy than fXa Ki using amidolytic substrates.