RESUMEN
The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.
Asunto(s)
Inhibidores del Factor Xa , Pirrolidinas/química , Pirrolidinas/farmacología , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Diseño de Fármacos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust candidate for progression towards clinical studies.
Asunto(s)
Benzazepinas/síntesis química , Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/química , Tetrahidroisoquinolinas/química , Administración Oral , Animales , Benzazepinas/administración & dosificación , Benzazepinas/farmacología , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Estructura Molecular , Ratas , Inhibidores de Serina Proteinasa/administración & dosificación , Tetrahidroisoquinolinas/administración & dosificación , Tetrahidroisoquinolinas/farmacologíaRESUMEN
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.
Asunto(s)
Anticoagulantes/química , Factor X/antagonistas & inhibidores , Pirrolidinonas/química , Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Factor X/metabolismo , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: Factor Xa (FXa) has been a target of considerable interest for drug development efforts aimed at suppressing thrombosis. In this report, a new orally active, small molecule, active-site directed FXa inhibitor, GW813893, has been profiled in a succession of in vitro and in vivo assays involved in its preclinical characterization as a potential antithrombotic therapeutic. METHODS: In vitro profiling of GW813893 consisted of assessing its inhibitory potential against FXa and a broad panel of related and unrelated enzymes and receptors. Additionally, the FXa inhibition potential of GW813893 was assessed in prothrombinase and plasma-based clotting assays. In vivo characterization of GW813893 consisted of thrombosis studies in a rat inferior vena cava model, a rat carotid artery thrombosis model, and a rabbit jugular thrombosis model. Bleeding studies were conducted in a rat tail transection model. Ex vivo determinations of compound effects on FX and clotting activity were also undertaken. RESULTS: GW813893 was more than 90-fold selective over all enzymes tested, and it inhibited FXa and prothrombinase activity with a Ki of 4.0 nM and 9.7 nM, respectively. In vivo, GW813893 concentration-dependently suppressed thrombotic activity in all models tested. The antithrombotic activity correlated with the suppression of plasma-based clotting activity and the inhibition of plasma FX activity (P < 0.02). Over the antithrombotic dose-range, an increased bleeding diathesis was not observed. CONCLUSION: These experiments demonstrate that GW813893 is a potent, selective, orally active inhibitor of FXa. The data suggest that GW813893 has robust antithrombotic potential at doses that have no detectable hemostasis liability. Collectively, the profile suggests that GW813893 has the preclinical pharmacology underpinnings of an oral antithrombotic therapeutic.
Asunto(s)
Inhibidores del Factor Xa , Fibrinolíticos/farmacología , Pirrolidinonas/farmacología , Sulfonamidas/farmacología , Administración Oral , Animales , Tiempo de Sangría , Pruebas de Coagulación Sanguínea , Trombosis de las Arterias Carótidas/tratamiento farmacológico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fibrinolíticos/uso terapéutico , Venas Yugulares , Masculino , Pirrolidinonas/uso terapéutico , Conejos , Ratas , Ratas Sprague-Dawley , Sulfonamidas/uso terapéutico , Vena Cava Inferior , Trombosis de la Vena/tratamiento farmacológicoRESUMEN
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Inhibidores del Factor Xa , Pirrolidinonas/química , Inhibidores de Serina Proteinasa/química , Animales , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacología , Ratas , Ratas Sprague-Dawley , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.
Asunto(s)
Inhibidores del Factor Xa , Pirrolidinonas/química , Pirrolidinonas/farmacología , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Animales , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Diseño de Fármacos , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.
Asunto(s)
Inhibidores del Factor Xa , Fibrinolíticos/farmacología , Morfolinas/farmacología , Sulfonamidas/farmacología , Trombina/antagonistas & inhibidores , Animales , Perros , Fibrinolíticos/síntesis química , Fibrinolíticos/química , Modelos Moleculares , Estructura Molecular , Morfolinas/síntesis química , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
Structure-based design (SBD) is a challenging endeavour since even localised SAR can hardly ever be explained by the variation of just one dominating factor. Here, we present a rare example where structural information combined with ab initio calculations clearly indicate that the observed difference in biological activity is dominated by conformational effects. The learnings discussed are successfully put to the test and have the potential to be of general use as a qualitative guide in SBD efforts.
Asunto(s)
Diseño de Fármacos , Sulfonamidas/química , Conformación Molecular , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.
Asunto(s)
Anticoagulantes/síntesis química , Inhibidores del Factor Xa , Factor Xa/química , Morfolinas/síntesis química , Pirrolidinas/síntesis química , Sulfonamidas/síntesis química , Animales , Anticoagulantes/química , Anticoagulantes/farmacología , Cristalografía por Rayos X , Perros , Femenino , Humanos , Ligandos , Masculino , Modelos Moleculares , Estructura Molecular , Morfolinas/química , Morfolinas/farmacología , Unión Proteica , Tiempo de Protrombina , Pirrolidinas/química , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Albúmina Sérica/química , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
Torsional scans of sulfonamide S-C bonds in small model systems of a series of arylsulfonamide factor Xa inhibitors were performed in order to investigate if conformational effects can help to rationalise the observed SAR. Computational results were in good agreement with the experimental data indicating that the sulfonamide conformation plays an important role in determining the activity in this particular series of factor Xa inhibitors.
Asunto(s)
Antitrombina III/química , Antitrombina III/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Conformación Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.
Asunto(s)
Alanina/química , Amidas/química , Antitrombina III/síntesis química , Antitrombina III/farmacología , Diseño de Fármacos , Pirroles/química , Anticoagulantes/síntesis química , Anticoagulantes/química , Anticoagulantes/metabolismo , Anticoagulantes/farmacología , Antitrombina III/química , Antitrombina III/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Factor Xa/química , Factor Xa/metabolismo , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.