Effect of SC 38249, a novel substituted imidazole, on platelet aggregation in vitro and in vivo.
SC 38249 [RS)-1-(2,3-bis-[(4-methoxyphenyl)methoxy]propyl)-1H-imidazole) caused dose-related inhibition of collagen-induced thromboxane A2 formation in human platelet rich plasma (IC50: 9.9 +/- 1.0 microM) accompanied by a dose-dependent increase in plasma PGE2. Broad inhibitory activity was evident against human platelet aggregatory and secretory responses in vitro. IC50 values of 11.9 +/- 1.9 microM (0.64 mM arachidonic acid), 18.3 +/- 3.8 microM (0.5 microgram ml-1 collagen) and 37.6 +/- 6.1 microM (25 nM Paf-acether) were obtained against maximum increase in PRP light transmission achieved by each agonist. Although less potent, SC 38249 retained significant inhibitory activity against PRP responses induced by a higher (3.0 micrograms ml-1) concentration of collagen (IC50: 272.5 +/- 24.6 microM), and against Paf-acether-induced responses in PRP pre-treated with 10 microM indomethacin (I.C.50: 192.0 +/- 16.1 microM). Experimental animal studies confirmed the in vitro anti-aggregatory efficacy of SC 38249, since significant inhibitory activity was observed against Paf-acether and ADP-induced responses in dog PRP ex vivo, anti-Forssman antibody-induced thrombocytopenia in anaesthetized guinea pigs, and collagen-induced intravascular aggregation in anaesthetized rabbits. Thus, SC 38249 is a novel thromboxane synthase inhibitor which possesses interesting anti-aggregatory properties which cannot wholly be attributed to prevention of platelet thromboxane A2 formation.
D000293:Adolescent; D000328:Adult; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D015232:Dinoprostone; D004285:Dogs; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D011458:Prostaglandins E / Q000097:blood; D011817:Rabbits; D013921:Thrombocytopenia / Q000517:prevention & control; D013928:Thromboxane A2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D001095:Arachidonic Acids; D007093:Imidazoles; D011458:Prostaglandins E; D016718:Arachidonic Acid; D013928:Thromboxane A2; C053318:1-(2,3-bis((4-methoxyphenyl)methoxy)propyl)-1H-imidazole; D003094:Collagen; D013930:Thromboxane-A Synthase; D015232:Dinoprostone