Pyrido[2,3-d]pyrimidine angiotensin II antagonists.
A series of pyrido[2,3-d]pyrimidine angiotensin II (A II) antagonists was synthesized and tested for antagonism of A II. Compounds with a biphenylyltetrazole pharmacophore and small alkyl groups at the 2- and 4-positions of the pyridopyrimidine ring were found to be the most potent in an AT1 receptor binding assay and in blocking the A II pressor response in anesthetized, ganglion-blocked A II-infused rats. 5,8-Dihydro-2,4-dimethyl-8-[(2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl)methyl]pyrido[2,3-d]pyrimidin-7(6H)-one (4a) was one of the more potent compounds in the binding assay and was the most efficacious compound in the A II-infused rat model. Further study of 4a in Goldblatt (2K-1C) rats showed the compound to have oral bioavailability and to be an efficacious and potent compound in a high renin form of hypertension.
Ellingboe
J W
JW
Wyeth-Ayerst Research, Division of Exploratory Chemistry, Princeton, New Jersey 08543-8000.
Antane
M
M
Nguyen
T T
TT
Collini
M D
MD
Antane
S
S
Bender
R
R
Hartupee
D
D
White
V
V
McCallum
J
J
Park
C H
CH
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011311:Pressoreceptors / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
D011725:Pyridines; D011743:Pyrimidines; D013777:Tetrazoles; C086167:tasosartan