Nonpeptide angiotensin II antagonists derived from 4H-1,2,4-triazoles and 3H-imidazo[1,2-b][1,2,4]triazoles.
By a variety of synthetic routes, we have synthesized a series of 3,4,5-trisubstituted 4H-1,2,4-triazoles and a related series of 3H-imidazo[1,2-b][1,2,4]triazoles and evaluated them in vitro and in vivo as angiotensin II (AII) antagonists. Principal efforts focused on triazoles bearing an n-alkyl substitutent at C3 and a 4-[(2-carboxybenzoyl)amino]benzyl, (2'-carboxybiphenyl-4-yl)methyl, or [2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl side chain at N4. Among numerous variations at C5, benzylthio groups gave the best potency. Particularly noteworthy was 3-n-butyl-5-[(2-carboxybenzyl)thio]-4-[[2'-(1H-tetrazol-5-yl )biphenyl-4 - yl]methyl]-4H-1,2,4-triazole (71, IC50 1.4 nM), which blocked the AII pressor response in conscious rats at 0.3 mg/kg iv with a duration of action of approximately 6 h, similar to that of DuP 753. Although 71 was active orally only at a 10-fold higher dose level, good oral bioavailability was demonstrated for a monoacidic analogue 62. Most potent among the bicyclic derivatives was 2-n-butyl-5,6-dimethyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]meth yl]- 3H-imidazo[1,2-b][1,2,4]triazole (93, IC50 7.8 nM). The effects of hydrophobic, hydrogen-bonding, and ionic interactions with the AT1 receptor are considered.
Merck Research Laboratories, Rahway, New Jersey 07065.
W T
WT
Ashton
C L
CL
Cantone
L L
LL
Chang
S M
SM
Hutchins
R A
RA
Strelitz
M
M
MacCoss
R S
RS
Chang
V J
VJ
Lotti
K A
KA
Faust
T B
TB
Chen
D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D011945:Receptors, Angiotensin; D014230:Triazoles; D000804:Angiotensin II