2-(Alkylamino)nicotinic acid and analogs. Potent angiotensin II antagonists.
A series of pyridines and other six-membered ring heterocycles connected to a biphenyltetrazole with a -CH2-NR'-link (1) were discovered to be potent angiotensin II antagonists. In the pyrimidine carboxylic acid series (W = CR, X = N, Y = CH, Z = COOH), compounds with an alkyl group (R') on the exocyclic nitrogen were much more potent than compounds with an alkyl group (R) on the heterocyclic ring. The corresponding pyridine, pyridazine, pyrazine, and 1,2,4-triazine carboxylic acids also showed potent in vitro angiotensin II antagonism. The pyridine (W, X, Y = CH, Z = COOH, R' = n-C3H7) demonstrated potent in vitro activity (pA2 = 10.10, rabbit aorta, and Ki = 0.61 nM, receptor binding in rat liver) as well as exceptional oral antihypertensive activity and bioavailability. Any nonacidic replacement for the carboxylic acid was detrimental for activity.
Winn
M
M
Abbott Laboratories, Pharmaceutical Products Division, Abbott Park, Illinois 60064.
De
B
B
Zydowsky
T M
TM
Altenbach
R J
RJ
Basha
F Z
FZ
Boyd
S A
SA
Brune
M E
ME
Buckner
S A
SA
Crowell
D
D
Drizin
I
I
D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001682:Biological Availability; D007457:Iodine Radioisotopes; D008099:Liver / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009525:Niacin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009539:Nicotinic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007457:Iodine Radioisotopes; D009539:Nicotinic Acids; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C081174:A 81988; D009525:Niacin