Nonpeptide angiotensin II antagonists derived from 4H-1,2,4-triazoles and 3H-imidazo[1,2-b][1,2,4]triazoles

Article abstract of DOI:10.1021/jm00057a009

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- carboxybenzyl)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.