Selective thromboxane synthetase inhibitors. 1. 1-[(Aryloxy)alkyl]-1H-imidazoles.
1-(2-Phenoxyethyl)-1H-imidazole was found to be an inhibitor of thromboxane (TxA2) synthetase, but it also inhibited the adrenal cytochrome P-450 enzyme steroid 11 beta-hydroxylase. The preparation of a series of analogues is described, and activity against TxA2 synthetase, PGI2 synthetase, cyclooxygenase, and steroid 11 beta-hydroxylase is discussed. Potency against TxA2 synthetase was increased by introduction of a carboxyl group at a suitable distance from the imidazole ring. A distance of 8.1-8.8 A between N-1 of the imidazole and the carboxyl carbon was found to be optimal. Introduction of a carboxyl group also had the effect of reducing activity against steroid 11 beta-hydroxylase. The most potent and selective compound was found to be 4-[2-(1H-imidazol-1-yl) ethoxy]benzoic acid (14).
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D016861:Cyclooxygenase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases; D008297:Male; D012756:Sheep; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D013252:Steroid 11-beta-Hydroxylase; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase