title: Structural evolution and pharmacology of a novel series of triacid angiotensin II receptor antagonists.
abstract: cis-4-(4-Phenoxy)-1-[1-oxo-2(R)-[4-[(2-sulfobenzoyl)amino)-1H- imidazol-1-yl]octyl]-L-proline derivatives represent 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, cis-4-[4-(phosphonomethyl)phenoxy]-1-[1-oxo-2(R)-[4-[(2-sulfobenzoyl+ ++) amino]-1H-imidazol-1-yl]octyl]-L-proline (1e), inhibited the pressor response to exogenously administered Ang II for periods up to 8 h following oral dosing. The antihypertensive activity of 1e was evaluated in the Lasix-pretreated conscious spontaneously hypertensive rat (SHR) where it produced a dose-dependent fall in blood pressure following oral dosing lasting > 12 h. Antagonists such as 1e may serve as useful therapeutic agents for the treatment of hypertension as well as for studying the role of Ang II in various disease states.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: A D
authors.initials: AD
authors.lastname: Palkowitz
authors.forename: M I
authors.initials: MI
authors.lastname: Steinberg
authors.forename: K J
authors.initials: KJ
authors.lastname: Thrasher
authors.forename: J K
authors.initials: JK
authors.lastname: Reel
authors.forename: K L
authors.initials: KL
authors.lastname: Hauser
authors.forename: K M
authors.initials: KM
authors.lastname: Zimmerman
authors.forename: S A
authors.initials: SA
authors.lastname: Wiest
authors.forename: C A
authors.initials: CA
authors.lastname: Whitesitt
authors.forename: R L
authors.initials: RL
authors.lastname: Simon
authors.forename: W
authors.initials: W
authors.lastname: Pfeifer
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D000804:Angiotensin II