Synthesis and structure-activity relationships of nonpeptide, potent triazolone-based angiotensin II receptor antagonists.
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.
Huang
H C
HC
Department of Chemistry, Searle R&D, St. Louis, Missouri 63198.
Reitz
D B
DB
Chamberlain
T S
TS
Olins
G M
GM
Corpus
V M
VM
McMahon
E G
EG
Palomo
M A
MA
Koepke
J P
JP
Smits
G J
GJ
McGraw
D E
DE
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
D057911:Angiotensin Receptor Antagonists; D013777:Tetrazoles; D014230:Triazoles; C075064:SC 51316