Synthesis and structure-activity relationships of nonpeptide, potent triazolone-based angiotensin II receptor antagonists
| Autor: | Horng-Chih Huang, Gillian M. Olins, V. M. Corpus, Timothy S. Chamberlain, Ellen G. Mcmahon, David B. Reitz, J P Koepke, D. E. Mcgraw, Maria A. Palomo, G J Smits |
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| Rok vydání: | 1993 |
| Předmět: |
Angiotensin receptor
Stereochemistry medicine.drug_class Substituent Tetrazoles Muscle Smooth Vascular chemistry.chemical_compound Angiotensin Receptor Antagonists Structure-Activity Relationship Drug Discovery medicine Structure–activity relationship Animals Binding site Receptor Binding Sites Chemistry Uterus Muscle Smooth Triazoles Receptor antagonist Angiotensin II Rats Molecular Medicine Female Rabbits |
| Zdroj: | Journal of medicinal chemistry. 36(15) |
| ISSN: | 0022-2623 |
| Popis: | 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 rabbit aortic 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. |
| Databáze: | OpenAIRE |
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