RESUMO
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.
Assuntos
Fosfolipases A/antagonistas & inibidores , Pirimidinonas/química , Pirimidinonas/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Fosfolipases A2 , Pirimidinonas/síntese química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The synthesis and phosphodiesterase (PDE) inhibitory profile of a series of imidazopyridines, including sulmazole and isomazole, on separated PDE isoenzymes are described. The results show that both sulmazole and isomazole are weak inhibitors of PDE III, and their inotropic activity is unlikely to be due to PDE III inhibition alone. Surprisingly, both compounds were found to be significant inhibitors of the cGMP specific isoenzyme, PDE V, and a series of simple 2-substituted phenylimidazo[4,5-b]pyridines have been made to investigate the SAR of PDE activity. This has been shown to be sensitive to chain length, polarity, and the nature of the heteroatom linking group. Potent PDE V inhibitors, many of which are also significant inhibitors of PDE IV, have been identified.