RESUMEN
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.
