Synthesis and Structure-Activity Relationships of Nonpeptide, Potent Triazolone-Based Angiotensin II Receptor Antagonists

Article abstract of DOI:10.1021/jm00067a015

2,5-Dibutyl-2,4-dihydro-4-<<2-(1H-tetrazol-5-yl)<1,1'-biphenyl>-4'-yl>methyl>-3H-1,2,4-triazol-3-one, SC-51316, was synthesized as a potent and orally active angiotensin II (AII) receptor antagonist with a long duration of action.To explore the lipophilic pocket in the AII receptor interacting with the substituent at the 2-position of triazolone-based antagonists, a series of compounds were prepared and evaluated for receptor binding affinity and antagonism of AII-contracted rabbitaortic rings.It has been found that the pocket is very spacious and can accommodate different sizes of lipophilic groups and various functionalities.Acidic groups generally result in a slight decrease in binding affinity.Branched chains are unfavorable.The freedom of rotation around C2-C3 in the flexible side chain is crucial for good binding.The 2-phenylethyl-substituted triazolone analogue exhibits the highest in vitro potency among all compounds that have been synthesized.