RESUMEN
The rationale for investigating conformationally restricted analogues of BW245C as DP-receptor ligands and the syntheses of three such racemic bicyclic imidazolidinone analogues are described. Compounds 7 (BW587C), 8 (BW480C85), and 9 (BW572C85) were found to be potent inhibitors of human platelet aggregation and selective DP-receptor agonists in washed platelet and jugular vein isolated tissue assays.
Asunto(s)
Butiratos/síntesis química , Butiratos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Receptores de Prostaglandina/agonistas , Animales , Presión Sanguínea/efectos de los fármacos , Butiratos/química , Diseño de Fármacos , Humanos , Hidantoínas/química , Hidantoínas/farmacología , Imidazoles/química , Venas Yugulares/efectos de los fármacos , Venas Yugulares/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Conejos , Ratas , Relación Estructura-ActividadRESUMEN
BW245C analogues which have 15'-keto, -oximino, -sulphinyl, -sulphonyl, -methyl, -1-adamantyl, 14'-hydroxy, 16'-hydroxy, 13'-14'-NH=CH, -NH-CH2, or -NH-CO groups have been synthesized and evaluated for their activity in inhibiting platelet aggregation and for their cardiovascular actions: the 13'-aza analogues 13 and 14 are more potent inhibitors of human platelet aggregation than BW245C (0.3, 0.6 and 0.2 x PGI2, respectively) and these inhibitory activities on platelet aggregation increase on incubation in vitro. The prostaglandin mimetic properties of 13 (BW68C) and 14 (BW361C) were studied in more detail and their platelet inhibitory and vasodilatory effects found to be of longer duration than those of BW245C. All other modifications to the omega-chain of BW245C led to less potent or inactive compounds.
Asunto(s)
Hidantoínas/síntesis química , Hidantoínas/farmacología , Inhibidores de Agregación Plaquetaria/síntesis química , Agregación Plaquetaria/efectos de los fármacos , Animales , Perros , Hemodinámica/efectos de los fármacos , Humanos , Técnicas In Vitro , Masculino , Inhibidores de Agregación Plaquetaria/farmacología , Conejos , Ratas , Ratas Wistar , Relación Estructura-Actividad , Vasodilatadores/síntesis química , Vasodilatadores/farmacologíaRESUMEN
A number of hydroperoxy (HPETE) and hydroxy (HETE) products of the lipoxygenase pathway of arachidonic acid metabolism are chemotactic and chemokinetic for human neutrophils. We have investigated the relative chemokinetic potency of some of these products on human, rat and rabbit neutrophils. The most potent lipoxygenase product studied was 5,12-dihydroxy-6,8,10-14-eicosatetraenoic acid (5,12-diHETE), which was maximally chemokinetic and chemotactic between 0.1 and 1.0ng/ml for the three species. The 5, 11 and 12-HPETEs and HETEs were chemokinetic, but less active by at least two orders of magnitude, for human and rabbit neutrophils at concentrations between 0.1 and 10micrograms/ml. 15-HPETE and 15-HETE were inactive on human leucoctes, and none of the monosubstituted products studied were chemokinetic for rat neutrophils. These results indicate that 5,12-diHETE may be an important mediator in the local accumulation of leucocytes in the inflammatory response.