RESUMO
The discovery and SAR of a series of potent renin inhibitors possessing a novel biaryl scaffold are described herein. Molecular modeling revealed that the cyclopropylamide spacer present in 1 can be replaced by a simple, substituted aromatic ring such as a toluene in 2. The resulting compounds exhibit subnanomolar renin IC(50) and good oral bioavailability in rats.
Assuntos
Bibenzilas/química , Inibidores Enzimáticos/química , Renina/antagonistas & inibidores , Administração Oral , Amidas/química , Animais , Bibenzilas/síntese química , Bibenzilas/farmacocinética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Ratos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.
Assuntos
Artrite Experimental/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Cães , Cobaias , Humanos , Macaca mulatta , Estrutura Molecular , Quinolinas/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4 , Relação Estrutura-Atividade , Sulfonamidas/farmacocinéticaRESUMO
Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact on the treatment of several degenerative diseases. Here we report the synthesis of reversible inhibitors via a solid-support palladium-catalyzed amination of 3-bromopyrazinones and the discovery of a pan-caspase reversible inhibitor.