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 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
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 series of benzoxazinone derivatives was designed and synthesized as factor Xa inhibitors. We demonstrated that the naphthyl moiety in the aniline-based compounds 1 and 2 can be replaced with benzene-fused heterobicycles and biaryls to give factor Xa inhibitors with improved trypsin selectivity. The P4 modifications lead to monoamidines which are moderately active. The benzoxazinones 41-45 are potent against factor Xa, retain the improved trypsin selectivity of the corresponding aniline-based compounds, and show strong antithrombotic effect dose responsively.