title: Synthesis and structure-activity relationships of nonpeptide, potent triazolone-based angiotensin II receptor antagonists.
abstract: 2,5-Dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4' - yl]methyl]-3H-1,2,4-triazol-3-one, SC-51316, was synthesized as a potent and orally active angiotensin II (AII) receptor antagonist with a long duration of action. To explore the lipophilic pocket in the AII receptor interacting with the substituent at the 2-position of triazolone-based antagonists, a series of compounds were prepared and evaluated for receptor binding affinity and antagonism of AII-contracted rabbit aortic rings. It has been found that the pocket is very spacious and can accommodate different sizes of lipophilic groups and various functionalities. Acidic groups generally result in a slight decrease in binding affinity. Branched chains are unfavorable. The freedom of rotation around C2-C3 in the flexible side chain is crucial for good binding. The 2-phenylethyl-substituted triazolone analogue exhibits the highest in vitro potency among all compounds that have been synthesized.
authors.affiliation: Department of Chemistry, Searle R&D, St. Louis, Missouri 63198.
authors.forename: H C
authors.initials: HC
authors.lastname: Huang
authors.forename: D B
authors.initials: DB
authors.lastname: Reitz
authors.forename: T S
authors.initials: TS
authors.lastname: Chamberlain
authors.forename: G M
authors.initials: GM
authors.lastname: Olins
authors.forename: V M
authors.initials: VM
authors.lastname: Corpus
authors.forename: E G
authors.initials: EG
authors.lastname: McMahon
authors.forename: M A
authors.initials: MA
authors.lastname: Palomo
authors.forename: J P
authors.initials: JP
authors.lastname: Koepke
authors.forename: G J
authors.initials: GJ
authors.lastname: Smits
authors.forename: D E
authors.initials: DE
authors.lastname: McGraw
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001665:Binding Sites; D005260:Female; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D057911:Angiotensin Receptor Antagonists; D013777:Tetrazoles; D014230:Triazoles; C075064:SC 51316