- and pyrroles as Thromboxane Synthetase Inhibitors

Article abstract of DOI:10.1021/jm00124a027

Several <(1H-imidazol-1-yl)methyl> and <(3-pyridinyl)methyl>pyrroles were prepared and evaluated in vitro as thromboxane synthetase inhibitors in human platelet aggregation studies.A number of structures, e.g. 10b,f,g,i (respective IC₅₀ values: 1 μM, 50 nM, 42 nM, 44 nM) showed superior in vitro inhibition of TXA₂ synthetase when compared to the standard dazoxiben (1).However, it was found that in vitro potency did not translate into nor correlate with in vivo activity when these compounds were evaluated in mice in a collagen-epinephrine-induced pulmonary thromboembolism model. (E)-1-Methyl-2-<(1H-imidazol-1-yl)methyl>-5-(2-carboxyprop-1-enyl)pyrrole (10b) was found to offer protection against collagen-epinephrine-induced mortality in mice, thereby demonstrating that oral administration is an effective route for absorption of this drug.Additional evidence for the oral effectiveness of 10b in lowering serum TXB₂ levels was obtained by performing ex vivo radioimmunoassay experiments with rats.A 13-week study of 10b in rats with reduced renal mass was conducted in order to evaluate the role of TXA₂ production in hypertension and renal dysfunction.Although serum and urinary TXB₂ levels in rats were found to be lowered during this study by 10b, the levels of urinary protein excretion remained comparable to that of the control group.