Nonpeptide angiotensin II antagonists: N-phenyl-1H-pyrrole derivatives are angiotensin II receptor antagonists

A series of 5-[1-[4-[(4,5-disubstituted-1H-imidazol-1-yl)methyl]- substituted]-1H-pyrrol-2-yl]-1H-tetrazoles and 5-[1-[4-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-substituted]- 1H-pyrrol-2-yl]-1H-tetrazoles were investigated as novel AT1-selective angiotensin II receptor antagonists. Computer-assi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1993, Vol.36 (1), p.101-110
Main Authors: Bovy, Philippe R., Reitz, David B., Collins, Joseph T., Chamberlain, Timothy S., Olins, Gillian M., Corpus, Valerie M., McMahon, Ellen G., Palomo, Maria A., Koepke, John P., Smits, Glen J., McGraw, Dean E., Gaw, Jeffrey F.
Format: Article
Language:English
Subjects:
angiotensin II
Angiotensin II - antagonists & inhibitors
Angiotensin Receptor Antagonists
Animals
antagonists
aorta
Binding Sites - drug effects
Chemistry
derivatives
Exact sciences and technology
Female
Heterocyclic compounds
Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings
Male
Muscle, Smooth, Vascular - drug effects
N-phenyl-1-H pyrrole
nonpeptide
Organic chemistry
Preparations and properties
Pyrroles - chemical synthesis
Pyrroles - metabolism
Pyrroles - pharmacology
Rabbits
Rats
Rats, Sprague-Dawley
receptors
Receptors, Angiotensin - metabolism
Structure-Activity Relationship
synthesis
uterus
Uterus - drug effects
Uterus - metabolism
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Summary:A series of 5-[1-[4-[(4,5-disubstituted-1H-imidazol-1-yl)methyl]- substituted]-1H-pyrrol-2-yl]-1H-tetrazoles and 5-[1-[4-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-substituted]- 1H-pyrrol-2-yl]-1H-tetrazoles were investigated as novel AT1-selective angiotensin II receptor antagonists. Computer-assisted modeling techniques were used to evaluate structural parameters in comparison to the related biphenyl system. New synthetic procedures have been developed to prepare the novel compounds. The best antagonists in this series had IC50 values (rat uterine membrane receptor binding) in the 10(-8) M range and corresponding pA2 in isolated organ assay (rabbit aorta rings). Structure-activity relationships indicate some similarities with the finding in the biphenyl system. Substitution on the pyrrole ring modulates activity. Compound 5 antagonized angiotensin-induced blood pressure increase when administered to conscious rat at 30 mg/kg per os.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00053a013