title: Thromboxane synthetase inhibitors and antihypertensive agents. 3. N-[(1H-imidazol-1-yl)alkyl]heteroaryl amides as potent enzyme inhibitors.
abstract: The title compounds were prepared as the heterocyclic analogues of thromboxane (TX) synthetase inhibitors and antihypertensive agents previously reported from our laboratories. These compounds were at least as active TX synthetase inhibitors as their benzene isosteres with the indole derivatives 50-55 having the most potent enzyme inhibiting activity measured to date in our laboratories. The best compound, 54, is more than 200-fold more potent than the standard, dazoxiben. In contrast, the antihypertensive activity of these series of compounds was no better than their benzene counterparts and is far lower than the isoindoledione derivatives prepared in a related series. The structure-activity relationship results from this study were similar to our previous observations and include the fact that the amide moiety effectively replaces a carboxylic acid for potent TX synthetase inhibition and that a four to six methylene unit separation (approximately 8.5 A) between amide and imidazole moieties achieves maximal activity.
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D001572:Benzofurans; D005663:Furans; D006571:Heterocyclic Compounds; D007093:Imidazoles; D007211:Indoles; D011725:Pyridines; D013876:Thiophenes; D013930:Thromboxane-A Synthase