RESUMO
Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.
Assuntos
Isoxazóis/síntese química , Inibidores da Agregação Plaquetária/síntese química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Sulfonamidas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Humanos , Técnicas In Vitro , Injeções Intravenosas , Isoxazóis/química , Isoxazóis/metabolismo , Isoxazóis/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Fatores de TempoRESUMO
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.
Assuntos
Isoxazóis/química , Inibidores da Agregação Plaquetária/síntese química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Administração Oral , Animais , Plaquetas/efeitos dos fármacos , Cães , Desenho de Fármacos , Feminino , Isoxazóis/administração & dosagem , Isoxazóis/farmacologia , Macaca mulatta , Masculino , Modelos Químicos , Papio , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacologiaRESUMO
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.