RESUMO
Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.
Assuntos
Oxazóis/síntese química , Piridonas/síntese química , Receptores de Prostaglandina E Subtipo EP3/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Estrutura Molecular , Oxazóis/química , Oxazóis/farmacologia , Ligação Proteica/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP3/química , Relação Estrutura-AtividadeRESUMO
High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.
