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-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.
Bovy
P R
PR
Cardiovascular Diseases Research, Searle & Company, St. Louis, Missouri 63198.
Reitz
D B
DB
Collins
J T
JT
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
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D005260:Female; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D011758:Pyrroles; D011945:Receptors, Angiotensin; D000804:Angiotensin II