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
Substituted pyrazoles, 1,2,4-triazoles, and tetrazoles are good surrogates for cis-amide bonds in a series of boronate ester thrombin inhibitors.
Assuntos
Amidas/farmacologia , Ácidos Borônicos/farmacologia , Pirazóis/farmacologia , Tetrazóis/farmacologia , Trombina/antagonistas & inibidores , Trombina/química , Triazóis/farmacologia , Amidas/química , Sítios de Ligação , Ácidos Borônicos/química , Cristalografia por Raios X , Indicadores e Reagentes , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Estereoisomerismo , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química , Triazóis/síntese química , Triazóis/químicaRESUMO
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
Acyl-CoA:cholesterol acyltransferase (ACAT) is the primary enzyme involved in intracellular cholesterol esterification. Arterial wall infiltration by macrophages and subsequent uncontrolled esterification of cholesterol leading to foam cell formation is believed to be an important process which leads to the development of fatty streaks. Inhibitors of the ACAT enzyme may retard this atherogenic process. We have recently discovered a series of imidazoles which are potent in vitro ACAT inhibitors in the J774 macrophage cell culture assay. This paper will describe the design, synthesis, and structure--activity relationship for this very potent series of compounds.
Assuntos
Macrófagos/enzimologia , Esterol O-Aciltransferase/antagonistas & inibidores , Animais , Linhagem Celular , Desenho de Fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Isoenzimas/antagonistas & inibidores , Camundongos , Microssomos Hepáticos/enzimologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N'-(2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2- yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.