SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NONPEPTIDE, POTENT TRIAZOLONE-BASED ANGIOTENSIN-II RECEPTOR ANTAGONISTS

[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 angioten sin II (AII) receptor antagonist with a long duration of action. To ex plore the lipophilic pocket in the AII receptor interacting with the s ubstituent at the 2-position of triazolone-based antagonists, a series of compounds were prepared and evaluated for receptor binding affinit y and antagonism of AII-contracted rabbit aortic rings. It has been fo und that the pocket is very spacious and can accommodate different siz es of lipophilic groups and various functionalities. Acidic groups gen erally result in a slight decrease in binding affinity. Branched chain s are unfavorable. The freedom of rotation around C2-C3 in the flexibl e side chain is crucial for good binding. The 2-phenylethyl-substitute d triazolone analogue exhibits the highest in vitro potency among all compounds that have been synthesized.