RESUMO
Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.
Assuntos
Amidas/química , Desenho de Fármacos , Isoxazóis/química , Quinazolinonas/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Cães , Meia-Vida , Haplorrinos , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.