RESUMO
ATP-citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Inhibitors of the enzyme represent a potentially novel class of hypolipidemic agent, which are anticipated to have combined hypocholesterolemic and hypotriglyceridemic properties. A series of 2-substituted butanedioic acids have been designed and synthesized as inhibitors of the enzyme. The best compounds, 58, 68, 71, 74 have reversible Ki's in the 1-3 microM range against the isolated rat enzyme. As representative of this compound class, 58, has been shown to exert its inhibitory action through a mainly competitive mechanism with respect to citrate and a noncompetitive one with respect to CoA. None of the inhibitors were able to inhibit cholesterol and/or fatty acid synthesis in HepG2 cells. This has been attributed to the adverse physicochemical properties of the molecules leading to a lack of cell penetration. Despite this, a lead structural class of compound has been identified with the potential for modification into potent, cell-penetrant, and efficacious inhibitors of ATP-citrate lyase.
Assuntos
ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Hipolipemiantes/síntese química , Animais , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipolipemiantes/farmacologia , Cinética , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Potent 3-anilino-4-arylmaleimide glycogen synthase kinase-3 (GSK-3) inhibitors have been prepared using automated array methodology. A number of these are highly selective, having little inhibitory potency against more than 20 other protein kinases.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Maleimidas/farmacologia , Animais , Transtorno Bipolar/tratamento farmacológico , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Quinases da Glicogênio Sintase , Humanos , Maleimidas/síntese química , Maleimidas/química , Maleimidas/uso terapêutico , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Aryl hydroxylamine derivatives have been synthesised that are some of the most potent inhibitors of hCMV protease prepared to date (IC50 14-60 nM). Mass spectrometry studies indicate that oxazinone derived hydroxylamines inhibit the enzyme by acylation of Ser132 whereas non-oxazinone derived hydroxylamines appear to inhibit via formation of a sulfinanilide at Cys138.
Assuntos
Anti-Infecciosos/síntese química , Citomegalovirus/enzimologia , Hidroxilaminas/síntese química , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/síntese química , Sequência de Aminoácidos , Anti-Infecciosos/farmacologia , Sítios de Ligação , Infecções por Citomegalovirus , Humanos , Hidroxilaminas/farmacologia , Espectrometria de Massas , Dados de Sequência Molecular , Estrutura Molecular , Fragmentos de Peptídeos/química , Inibidores de Serina Proteinase/farmacologia , TripsinaRESUMO
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.