RESUMEN
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.
Asunto(s)
Cartílago/efectos de los fármacos , Cartílago/metabolismo , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Bovinos , Relación Dosis-Respuesta a Droga , Humanos , Interleucina-1/antagonistas & inhibidores , Interleucina-1/toxicidad , Isomerismo , Masculino , Metaloendopeptidasas/farmacología , Modelos Biológicos , Proteoglicanos/metabolismo , Piridinas/síntesis química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Acetatos/síntesis química , Inhibidores del Factor Xa , Fibrinolíticos/síntesis química , Isoxazoles/síntesis química , Acetatos/química , Acetatos/farmacología , Animales , Derivación Arteriovenosa Quirúrgica , Sitios de Unión , Compuestos de Bifenilo , Fibrinolíticos/química , Fibrinolíticos/farmacología , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Modelos Moleculares , Conejos , Relación Estructura-Actividad , Trombosis/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Isoxazoles/química , Inhibidores de Agregación Plaquetaria/síntesis química , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Administración Oral , Animales , Plaquetas/efectos de los fármacos , Perros , Diseño de Fármacos , Femenino , Isoxazoles/administración & dosificación , Isoxazoles/farmacología , Macaca mulatta , Masculino , Modelos Químicos , Papio , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacologíaRESUMEN
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.
Asunto(s)
Inhibidores del Factor Xa , Isoxazoles/farmacología , Inhibidores de Serina Proteinasa/farmacología , Animales , Cristalografía por Rayos X , Isoxazoles/química , Isoxazoles/farmacocinética , Modelos Moleculares , Conejos , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-Actividad , Trombosis/prevención & controlRESUMEN
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.