RESUMO
4-Aryl-3-pyridyl and 4-aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel isoxazolone five-membered heterocyclic core are described. Many showed sub-micromolar activity against lipopolysaccharide-induced TNF-alpha production.
Assuntos
Isoxazóis/síntese química , Isoxazóis/farmacologia , Pirimidinas/síntese química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Acetaldeído , Sítios de Ligação , Linhagem Celular , Humanos , Lipopolissacarídeos/farmacologia , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.
Assuntos
Inibidores Enzimáticos/síntese química , Pirazóis/síntese química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Humanos , Lipopolissacarídeos/farmacologia , Pirazóis/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/químicaRESUMO
2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.