Selective thromboxane synthetase inhibitors. 2. 3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoic acid and analogues.
The preparation of a series of 3-(1H-imidazol-1-ylmethyl)-1H-indole-1-alkanoic acids is described. Several compounds were found to be more potent thromboxane synthetase inhibitors than the corresponding analogues lacking an acidic substituent. In the cases examined, compounds had no significant activity against PGI2 synthetase or cyclooxygenase, and introduction of the carboxylic acid substituent led to a reduction in activity against adrenal steroid 11 beta-hydroxylase. Compound 21 strongly inhibited thromboxane formation after iv administration to anesthetized rabbits and oral administration to conscious dogs. The compound had a long duration of action, and marked inhibition of thromboxane production was observed 15 h after oral administration of 1 mg/kg to conscious dogs.
Cross
P E
PE
Dickinson
R P
RP
Parry
M J
MJ
Randall
M J
MJ
D000284:Administration, Oral; D000818:Animals; D016861:Cyclooxygenase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004285:Dogs; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007275:Injections, Intravenous; D019746:Intramolecular Oxidoreductases; D008297:Male; D011817:Rabbits; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D007211:Indoles; D013929:Thromboxane B2; D013928:Thromboxane A2; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D013252:Steroid 11-beta-Hydroxylase; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase