NONPEPTIDE ANGIOTENSIN-II ANTAGONISTS DERIVED FROM 4H-1,2,4-TRIAZOLES AND 3H-IMIDAZO[1,2-B][1,2,4]TRIAZOLES

By a variety of synthetic routes, we have synthesized a series of 3,4,5-trisubstituted 4H-1,2,4-triazoles and a related series of 3H-imidazo[1,2-b] [1,2,4]triazoles and evaluated them in vitro and in vivo as angiotensin II (AII) antagonists. Principal efforts focused on triazoles bearing an n-alkyl substituent at C3 and a 4-[(2-carboxybenzoyl)amino]benzyl, (2'-carboxybiphenyl-4-yl)methyl, or [2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl side chain at N4. Among numerous variations at C5, benzylthio groups gave the best potency. Particularly noteworthy was 3-n-butyl-5-[(2-carboxy-benzyl)thio]-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-4H-1,2,4-triazole (71, IC50 1.4 nM), which blocked the AII pressor response in conscious rats at 0.3 mg/kg iv with a duration of action of approximately 6 h, similar to that of DuP 753. Although 71 was active orally only at a 10-fold higher dose level, good oral bioavailability was demonstrated for a monoacidic analogue 62. Most potent among the bicyclic derivatives was 2-n-butyl-5,6-dimethyl-3-[ [2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[1,2-b][1,2,4]triazole (93, IC50 7.8 nM). The effects of hydrophobic, hydrogen-bonding, and ionic interactions with the AT1 receptor are considered.