Studies on nonpeptide angiotensin II receptor antagonists. II. Synthesis and biological evaluation of 5H-pyrazolo[1,5-b][1,2,4]triazole derivatives with a C-linked oxygen functional group at the 6-position.
2,7-Diethyl-5H-pyrazolo[1,5-b][1,2,4]triazole derivatives were synthesized and evaluated for activity as angiotensin II receptor antagonists. Replacement of the C-6 hydrogen with C-linked oxygen functional groups led to derivatives with increased in vitro activities. Among these compounds, 2,7-diethyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H- pyrazolo[1,5-b][1,2,4]triazole-6-carboxylic acid (2d) showed potent, insurmountable antagonism, but had poor oral potency against angiotensin II-induced pressor response in rats. In order to improve the oral activity, the carboxylic acid function of 2d was converted into a double ester. This modification afforded (+/-)-1-[(ethoxycarbonyl)oxy]ethyl 2,7-diethyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H- pyrazolo[1,5-b][1,2,4]-triazole-6-carboxylate (2f), which was orally active in rats, and produced a dose-dependent decrease in blood pressure when administered orally to conscious furosemide-treated dogs, with ca. 3-fold increased potency in comparison with the parent C-6 hydrogen compound.
Okazaki
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Suga
A
A
Watanabe
T
T
Kikuchi
K
K
Kurihara
H
H
Shibasaki
M
M
Fujimori
A
A
Inagaki
O
O
Yanagisawa
I
I
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D011720:Pyrazoles; D014230:Triazoles