Inhibition of thromboxane and 12-HPETE formation by dazoxiben and its two thiophenic acid-substituted derivatives

Abstract

LG 82-4-00 (5-(1-(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 TBX2. In thrombin (0.6 IU/ml)-stimulated, washed human platelet suspensions (WPS) the IC50 (μM) 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 μg/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 μM. At 100 μM, 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 82-4-01 are specific inhibitors of thromboxane synthetase in human platelets.