RESUMEN
Parallel synthesis and iterative optimization led to the discovery of a series of potent and specific factor Xa inhibitors demonstrating excellent in vitro activity with promising pharmacokinetics.
Asunto(s)
Antitrombina III/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores del Factor Xa , Antitrombina III/farmacología , Inhibidores Enzimáticos/química , Humanos , Conformación Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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
Anthranilamides 4 and 5 were designed and synthesized as selective and orally bioavailable factor Xa inhibitors. Structural modifications aimed at lowering their lipophilicity were performed at the central phenyl ring and at the S4 binding biphenyl region by incorporating water solublizing substituents. The resulting compounds (e.g., 7, 8, 14, 30a, and 32b) are highly potent in vitro, and show improved activity in human plasma-based thrombin generation assay.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Inhibidores del Factor Xa , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Trombosis/tratamiento farmacológico , Trombosis/prevención & controlRESUMEN
Compound 2 containing an aminomethylbenzoyl moiety as the S4 binding motif was synthesized in order to modulate hydrophlicity of anthranilamide-based factor Xa inhibitors with substituted biphenyl P4 groups. Structure-activity relationship studies around 2 have led to a series of potent factor Xa inhibitors which are highly active in the human plasma-based thrombin generation assay with 2XTG values less than 1 microM. Compound 55 shows strong antithrombotic activity in our rabbit deep vein thrombosis model, and also exhibits good oral bioavailability and a long half life in rats.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Inhibidores del Factor Xa , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Estructura Molecular , Conejos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Trombosis/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Inhibidores del Factor Xa , Oxazinas/síntesis química , Oxazinas/farmacología , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Técnicas In Vitro , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Conejos , Relación Estructura-Actividad , Trombina/metabolismo , Inhibidores de Tripsina/síntesis química , Inhibidores de Tripsina/farmacologíaRESUMEN
Monoamidine FXa inhibitors 3 were designed and synthesized. SAR studies and molecular modeling led to the design of conformationally constrained diaryl ethers 4 and 5, as well as benzopyrrolidinone 7 as potent FXa inhibitors. The monoamidines show high efficacy in a DVT model, but lack desirable oral bioavailability. The benzopyrrolidinone-based aminoisoquinolines 8 do not show significant improvement in oral bioavailability.