RESUMO
In search of antiinflammatory drugs with a new mechanism of action, U0126 was found to functionally antagonize AP-1 transcriptional activity via noncompetitive inhibition of the dual specificity kinase MEK with an IC50 of 0.07 microM for MEK 1 and 0.06 microM for MEK 2. U0126 can undergo isomerization and cyclization reactions to form a variety of products, both chemically and in vivo, all of which exhibit less affinity for MEK and lower inhibition of AP-1 activity than parent, U0126.
Assuntos
Butadienos/química , Inibidores Enzimáticos/química , Nitrilas/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Biotransformação , Butadienos/farmacocinética , Butadienos/farmacologia , Ciclização , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , NF-kappa B/antagonistas & inibidores , Nitrilas/farmacocinética , Nitrilas/farmacologia , Ratos , Fator de Transcrição AP-1/antagonistas & inibidoresRESUMO
Using isoxazoline XR299 (1a) as a starting point for the design of highly potent, long-duration GPIIb/IIIa antagonists, the effect of placing lipophilic substituents at positions alpha and beta to the carboxylate moiety was evaluated. Of the compounds studied, it was found that the n-butyl carbamate 24u exhibited superior potency and duration of ex vivo antiplatelet effects in dogs. Replacement of the benzamidin-4-yl moiety with alternative basic groups, elimination of the isoxazoline stereocenter, and reversal of the orientation of the isoxazoline ring resulted in lowered potency and/or duration of action.