The influence of selective thromboxane synthetase inhibition with a novel imidazole derivative, UK-38,485, on prostanoid formation in man.

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Abstract
UK-38,485 [3(1H-imidazole-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid], a novel imidazole derivative, was used in 2 clinical trials with healthy male subjects to study the influence of thromboxane synthetase inhibition on prostanoid formation. In an open pharmacokinetic study, UK-38,485 administered orally in doses of 10, 20, 40, 60 and 100 mg significantly reduced serum thromboxane (TXB2) concentrations. With lower doses (10 and 20 mg) peak inhibition of serum thromboxane occurred 2 h after dosing, with a mean percentage inhibition of 78 and 91%, respectively. For the higher doses (40, 60 and 100 mg) peak inhibition exceeded 99% 1 h after dosing. After 8 h the inhibition was dose related, ranging between 59 and 75%, and after 24 h between 0 and 35%. In a 2nd multiple-dose, double-blind, placebo-controlled, cross-over study, 50 mg UK-38,485 given twice daily for 1 wk selectively inhibited thromboxane synthetase. The excretion of 2,3-dinor-TXB2, the major urinary metabolite of endogenously formed thromboxane, was significantly reduced, whereas the urinary excretion of 2,3-dinor-5-keto-PGF1.alpha., the main metabolite of endogenous prostacyclin and the plasma concentrations of 6-keto-PGF1.alpha. showed no significant increases compared with levels in the placebo period. In platelet suspensions stimulated ex vivo with arachidonic acid and in serum of incubated whole blood, TXB2 concentrations were reduced and a significant redirection of endoperoxide metabolism to antiaggregatory and vasodilatory prostaglandins I2, E2, and d2 was demonstrated after the influence of UK-38,485. Platelet lipoxygenase metabolites were not measurably altered. The drug was well tolerated. In both studies, no clinically relevant changes in laboratory safety and hemodynamic parameters, bleeding or clotting time were observed. From the time course of the plasma drug concentrations, the inhibition of thromboxane synthesis, and the redirection of endoperoxide metabolism it can be concluded that UK-38,485 is rapidly absorbed and has a long-lasting effect on prostanoid formation.