RESUMO
The lipophilic 1-substituent in a series of 1-((amidolinked)-alkyl)-pyrimidones, inhibitors of recombinant lipoprotein-associated phospholipase A(2), has been modified to give inhibitors of high potency in human plasma and enhanced physicochemical properties. Phenylpiperazineacetamide derivative 23 shows very promising oral activity.
Assuntos
Inibidores Enzimáticos/farmacologia , Fosfolipases A/antagonistas & inibidores , Fosfolipases A/sangue , 1-Alquil-2-acetilglicerofosfocolina Esterase , Administração Oral , Animais , Inibidores Enzimáticos/síntese química , Humanos , Concentração Inibidora 50 , Taxa de Depuração Metabólica/fisiologia , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Coelhos , RatosRESUMO
From two related series of 2-(alkylthio)-pyrimidones, a novel series of 1-((amidolinked)-alkyl)-pyrimidones has been designed as nanomolar inhibitors of human lipoprotein-associated phospholipase A2. These compounds show greatly enhanced activity in isolated plasma. Selected derivatives such as compounds 51 and 52 are orally active with a good duration of action.
Assuntos
Inibidores Enzimáticos/farmacologia , Lipoproteínas/metabolismo , Fosfolipases A/antagonistas & inibidores , Pirimidinonas/farmacologia , Administração Oral , Animais , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Estrutura Molecular , Fosfolipases A/metabolismo , Fosfolipases A2 , Pirimidinonas/administração & dosagem , Pirimidinonas/química , CoelhosRESUMO
Starting from two weakly active hits from high throughput screening, a novel series of 2-(alkylthio)-pyrimidin-4-ones with high potency and selectivity for lipoprotein-associated phospholipase A2 has been designed. In contrast to previously known inhibitors, these have been shown to act by a non-covalent and substrate competitive mechanism.