RESUMO
anti-Substituted biaryl beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors that suffer from suboptimal selectivity and pharmacokinetics. This letter describes the substitution of the beta-methyl substituent with beta-polar substituents, culminating in the discovery of a beta-dimethylamide substituted phenylalanine derivative with an excellent potency, selectivity, and pharmacokinetic profile.
Assuntos
Dipeptidil Peptidase 4/química , Fenilalanina/síntese química , Fenilalanina/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Administração Oral , Animais , Glicemia/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dipeptidil Peptidase 4/metabolismo , Teste de Tolerância a Glucose , Humanos , Camundongos , Estrutura Molecular , Fenilalanina/farmacocinética , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato , Transativadores/metabolismo , Regulador Transcricional ERGRESUMO
We have synthesized a series of C7-piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones that are highly potent inhibitors of both p38MAP kinase activity and TNF-alpha release. The 4-aminopentamethylpiperidine naphthyridinone 5, which was designed to block metabolism at major 'hot spots', combined excellent inhibitory potency with good oral bioavailability in the rat.
