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
Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Fosfolipasas A/antagonistas & inhibidores , Pirimidinonas/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Animales , Inhibidores del Citocromo P-450 CYP2D6 , Inhibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Cinética , Fosfolipasas A/sangre , Fosfolipasas A2 , Pirimidinonas/química , Conejos , Proteínas Recombinantes/antagonistas & inhibidoresRESUMEN
The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.
Asunto(s)
Compuestos de Bifenilo/farmacología , Inhibidores Enzimáticos/farmacología , Lipoproteínas/metabolismo , Fosfolipasas A/antagonistas & inhibidores , Pirimidinonas/farmacología , Administración Oral , Animales , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/química , Compuestos de Bifenilo/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Fosfolipasas A/metabolismo , Pirimidinonas/administración & dosificación , Pirimidinonas/química , Pirimidinonas/metabolismo , Conejos , Relación Estructura-ActividadRESUMEN
A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects.
