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.
Subject(s)
Antihypertensive Agents/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Imidazoles/chemical synthesis , Thromboxane-A Synthase/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Animals , Antihypertensive Agents/pharmacology , Benzofurans/chemical synthesis , Benzofurans/pharmacology , Furans/chemical synthesis , Furans/pharmacology , Guinea Pigs , Heterocyclic Compounds/pharmacology , Imidazoles/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Male , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Rats, Inbred SHR , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
A series of N-[(1H-heteroaryl)alkyl]-1H-isoindole-1,3(2H)-diones were prepared as part of a continuing investigation into the biological properties of compounds that were both thromboxane synthetase inhibitors and potential antihypertensive agents. The most active thromboxane synthetase inhibition was found for the title imidazole derivatives wherein a hexyl or octyl chain separated the heterocyclic ends of the molecule (5,6) or with substitution on the isoindole portion of the molecule (18, 19, 21, 22, 25, 26). Compounds with shorter alkyl chain separations had good antihypertensive effects (1-5, 8-10, 19-22, 27-30). Butyl derivative 3 was chosen for further evaluation as a potential antihypertensive agent with thromboxane synthetase inhibitory properties.
Subject(s)
Antihypertensive Agents/therapeutic use , Imidazoles/toxicity , Indoles/toxicity , Thromboxane-A Synthase/antagonists & inhibitors , Triazoles/toxicity , Animals , Dogs , Epoprostenol/biosynthesis , Hypertension, Renal/drug therapy , Imidazoles/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
The title compounds were prepared to investigate their potential as thromboxane synthetase inhibitors as well as antihypertensive agents. Imidazoles VIII and triazoles X were prepared to examine the effects of aromatic substitution, chain length, and heterocycle substitution upon biological activity. Imidazoles VIII and triazoles X were thromboxane synthetase inhibitors that did not inhibit prostacyclin formation. The most interesting thromboxane synthetase inhibitors prepared were 4-chloro-, 4-(trifluoromethyl)-, and 4-bromobenzamide derivatives of (1H-imidazol-1-yl)alkylamines with C5-C8 alkyl chains separating the heterocycle from the amide moiety, while the most active antihypertensive agents were 3- or 4-chloro-, -bromo, or -(trifluoromethyl)benzamides with C3 alkyl chains. The best thromboxane synthetase inhibitors in this study were up to 10 times more potent than the standard, dazoxiben (UK 37,248).
