RESUMO
The synthesis, biological evaluation, and structure-activity relationships of a series of N-phenyl heteroaryl-fused isothiazolones are described. These isothiazolones have been shown to exhibit potent, dose-dependent inhibition of IL-1 beta-induced breakdown of proteoglycan in a cartilage organ culture assay. This effect is likely due to inhibition of MMP activation and a consequent reduction in MMP activity following IL-1 beta stimulation. Thus these compounds potentially represent simple, non-peptidic disease-modifying agents for the treatment of arthritic diseases. To examine the effects of structure on in vitro activity, three general features of the molecules were varied, substituents on the pendant N-phenyl group, the position of ring fusion to the isothiazolone, and substituents on the fused ring peri to the isothiazolone sulfur.
Assuntos
Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Bovinos , Relação Dose-Resposta a Droga , Humanos , Interleucina-1/antagonistas & inibidores , Interleucina-1/toxicidade , Isomerismo , Masculino , Metaloendopeptidases/farmacologia , Modelos Biológicos , Proteoglicanas/metabolismo , Piridinas/síntese química , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Thrombosis is a major cause of mortality in the industrialized world. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for prothrombin activation. We report a series of novel biaryl-substituted isoxazoline derivatives in which the biaryl moiety was designed to interact with the S(4) aryl-binding domain of the FXa active site. Several of the compounds herein have low nanomolar affinity for FXa, have good in vitro selectivity for FXa, and show potent antithrombotic efficacy in vivo. The three most potent compounds (33, 35, and 37) have inhibition constants for human FXa of 3.9, 2.3, and 0.83 nM, respectively, and ID(50)'s ranging from 0.15 to 0.26 micromol/kg/h in the rabbit arterio-venous thrombosis model.
Assuntos
Acetatos/síntese química , Inibidores do Fator Xa , Fibrinolíticos/síntese química , Isoxazóis/síntese química , Acetatos/química , Acetatos/farmacologia , Animais , Derivação Arteriovenosa Cirúrgica , Sítios de Ligação , Compostos de Bifenilo , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Modelos Moleculares , Coelhos , Relação Estrutura-Atividade , Trombose/tratamento farmacológicoRESUMO
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
3,4,5-Trisubstituted isoxazolines (2) and isoxazoles (3) were prepared and evaluated for their in vitro and in vivo antithrombotic efficacy. They were compared to 3,5,5-trisubstituted isoxazolines (1) for Factor Xa selectivity and potency. They were also compared in an arterio-venous (A-V) shunt model of thrombosis.
Assuntos
Inibidores do Fator Xa , Isoxazóis/farmacologia , Inibidores de Serina Proteinase/farmacologia , Animais , Cristalografia por Raios X , Isoxazóis/química , Isoxazóis/farmacocinética , Modelos Moleculares , Coelhos , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-Atividade , Trombose/prevenção & controleRESUMO
The selective inhibition of coagulation factor Xa has emerged as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe highly potent benzamidine factor Xa inhibitors based on a vicinally-substituted heterocyclic core.