STRUCTURAL EVOLUTION AND PHARMACOLOGY OF A NOVEL SERIES OF TRIACID ANGIOTENSIN-II RECEPTOR ANTAGONISTS

fobenzoyl)amino)-1H-imidazol-1-yl]octyl]-L-proline derivatives represe nt a novel class of potent nonpeptide angiotensin II (Ang II) receptor antagonists. These compounds evolved from directed structure-activity relationship (SAR) studies on a lead identified by random screening. Further SAR studies revealed that acidic modification of the 4-phenoxy ring system produced a series of triacid derivatives possessing oral activity in pithed rats. The most potent compound, fobenzoyl)amino]-1H -imidazol-1-yl]octyl]-L-proline (1e), inhibited the presser response t o exogenously administered Ang II for periods up to 8 h following oral dosing. The antihypertensive activity of 1e was evaluated in the Lasi x-pretreated conscious spontaneously hypertensive rat (SHR) where it p roduced a dose-dependent fall in blood pressure following oral dosing lasting >l2 h. Antagonists such as 1e may serve as useful therapeutic agents for the treatment of hypertension as well as for studying the r ole of Ang II in various disease states.