RESUMEN
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
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
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.