Inhibition of thromboxane and 12-HPETE formation by dazoxiben and its two thiophenic acid-substituted derivatives.
LG 82-4-00 (5-(2-(1-imidazolyl)-ethoxy)-thiophene-2-carboxylate) and LG 82-4-01 (4-chloro-thiophenic-substituted derivative) were examined for specific inhibition of thromboxane (TX) synthetase. Thromboxane formation was measured by a radioimmunoassay specific for TXB2. In thrombin (0.6 IU/ml)-stimulated, washed human platelet suspensions (WPS) the IC50 (microM) for inhibition of TX formation were 1.1 (LG 82-4-00), 1.3 (LG 82-4-01) and 0.7 (dazoxiben). LG 82-4-00, LG 82-4-01 and dazoxiben also inhibited collagen (0.6-2.5 micrograms/ml)-induced TXB2 formation and platelet aggregation in human platelet-rich plasma. Neither LG 82-4-00 nor LG 82-4-01 had vasoconstrictor, proaggregatory or TX antagonistic activity or affected primary wave ADP aggregation. There was less than 10% inhibition of PGI2 formation from bovine coronary artery slices with concentrations up to 100 microM. At 100 microM, dazoxiben inhibited thrombin-induced 12-HPETE formation in WPS by 81 +/- 10% whereas LG 82-4-00 and LG 82-4-01 were much less active. These data indicate that LG 82-4-00 and LG 82-4-01 are specific inhibitors of thromboxane synthetase in human platelets.
D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D011464:Epoprostenol / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D015289:Leukotrienes; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D013876:Thiophenes / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000096:biosynthesis; D014661:Vasoconstriction / Q000187:drug effects
D001095:Arachidonic Acids; D007093:Imidazoles; D015289:Leukotrienes; D013876:Thiophenes; D013931:Thromboxanes; C029166:dazoxiben; C021201:12-HPETE; C046339:LG 82-4-00; C046340:LG 82-4-01; D011464:Epoprostenol; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase