Journal of Medicinal Chemistry p. 2172 - 2181 (1993)
Update date:2022-09-26
Topics:
Huang, Horng-Chih
Reitz, David B.
Chamberlain, Timothy S.
Olins, Gillian M.
Corpus. Valerie M.
et al.
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.
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