RESUMO
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.
Assuntos
Inibidores Enzimáticos/farmacologia , Fosfolipases A/antagonistas & inibidores , Pirimidinonas/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase , Animais , Inibidores do Citocromo P-450 CYP2D6 , Inibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Cinética , Fosfolipases A/sangue , Fosfolipases A2 , Pirimidinonas/química , Coelhos , Proteínas Recombinantes/antagonistas & inibidoresRESUMO
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.
Assuntos
Compostos de Bifenilo/farmacologia , Inibidores Enzimáticos/farmacologia , Lipoproteínas/metabolismo , Fosfolipases A/antagonistas & inibidores , Pirimidinonas/farmacologia , Administração Oral , Animais , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Fosfolipases A/metabolismo , Pirimidinonas/administração & dosagem , Pirimidinonas/química , Pirimidinonas/metabolismo , Coelhos , Relação Estrutura-AtividadeRESUMO
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.