RESUMEN
Several P4 domain derivatives of the general d-phenylglycinamide-based scaffold (2) were synthesized and evaluated for their ability to bind to the serine protease factor Xa. Some of the more potent compounds were evaluated for their anticoagulant effects in vitro. A select subset containing various P1 indole constructs was further evaluated for their pharmacokinetic properties after oral administration to rats.
Asunto(s)
Antitrombina III/síntesis química , Antitrombina III/farmacología , Glicina/análogos & derivados , Anticoagulantes/síntesis química , Anticoagulantes/química , Anticoagulantes/farmacología , Antitrombina III/química , Cristalografía por Rayos X , Factor Xa/química , Factor Xa/metabolismo , Glicina/síntesis química , Glicina/química , Glicina/farmacología , Humanos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
Analogs to a series of D-phenylglycinamide-derived factor Xa inhibitors were discovered. It was found that the S4 amide linkage can be replaced with an ether linkage to reduce the peptide character of the molecules and that this substitution leads to an increase in binding affinity that is not predicted based on modeling. Inhibitors which incorporate ether, amino, or alkyl S4 linkage motifs exhibit similar levels of binding affinity and also demonstrate potent in vitro functional activity, however, binding affinity in this series is strongly dependent on the nature of the S1 binding element.
Asunto(s)
Anticoagulantes/farmacología , Inhibidores del Factor Xa , Glicina/análogos & derivados , Inhibidores de Serina Proteinasa/farmacología , Anticoagulantes/química , Cristalografía por Rayos X , Etanolaminas , Glicina/química , Modelos Moleculares , Péptidos/química , Inhibidores de Serina Proteinasa/químicaRESUMEN
SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays.
Asunto(s)
Antitrombina III/síntesis química , Inhibidores del Factor Xa , Colorantes Fluorescentes/farmacología , ortoaminobenzoatos/farmacología , Anticoagulantes/química , Antitrombina III/química , Sitios de Unión , Química Farmacéutica/métodos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Colorantes Fluorescentes/síntesis química , Humanos , Cinética , Modelos Químicos , Conformación Molecular , Relación Estructura-Actividad , ortoaminobenzoatos/síntesis químicaRESUMEN
The authors show by illustration that procedures used to validate the reliability of single-concentration high-throughput screens such as the signal window and Z' factor do not ensure sufficient reliability in potency estimates from concentration response assays. They develop the minimum significant ratio as a statistical parameter to characterize the fold change between 2 compounds run in the same experiment that can be considered a real difference and use this parameter to characterize the reliability of the assay. They adapt methods described by Bland and Altman to develop a simple set of 2 experiments to estimate the minimum significant ratio and show that this protocol can identify assays that lack reproducibility. The methods are then extended to validate the equivalency of the same assay run by multiple laboratories.
Asunto(s)
Modelos Estadísticos , Reproducibilidad de los Resultados , Factor Xa/metabolismo , Inhibidores del Factor XaRESUMEN
Several non-amidino S1 derivatives of the 1,2-diaminobenzene-based scaffold (4) were synthesized and evaluated for their ability to bind to the active site and inhibit the human protease factor Xa. A subset of these compounds were also evaluated for their anticoagulant effects in human plasma as measured by prothrombin time (PT).
Asunto(s)
Anticoagulantes/síntesis química , Derivados del Benceno/síntesis química , Inhibidores del Factor Xa , Anticoagulantes/farmacología , Derivados del Benceno/farmacología , Sitios de Unión , Coagulación Sanguínea/efectos de los fármacos , Factor Xa/metabolismo , Humanos , Modelos Moleculares , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Unión Proteica , Tiempo de Protrombina , Relación Estructura-ActividadRESUMEN
A novel isonitrile derivative was synthesized and used in an Ugi four component coupling reaction to explore aryl group substitution effects on inhibition of the coagulation cascade serine protease factor Xa.