2-(ALKYLAMINO)NICOTINIC ACID AND ANALOGS - POTENT ANGIOTENSIN-II ANTAGONISTS

A series of pyridines and other six-membered ring heterocycles connect ed to a biphenylyltetrazole 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 compo unds with an alkyl group (R) on the heterocyclic ring. The correspondi ng 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 acti vity (pA2 = 10. 10, rabbit aorta, and K(i) = 0.61 nM, receptor binding in rat fiver) as well as exceptional oral antihypertensive activity a nd bioavailability. Any nonacidic replacement for the carboxylic acid was detrimental for activity.