期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 -, 页码 358-374出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.07.040
关键词
Synthesis; Angiotensin II receptor blockers; N-substituted 5-butylimidazole derivatives; Antihypertensive activity; Molecular docking
资金
- research program PRAXE B-EPAN
- General Secretariat of Research and Technology of Greece
- Ministry of Development
- ELDRUG SA
- VIANEX SA
A convenient and facile synthesis, in silica docking studies and in vitro biological evaluation of N-substituted 5-butylimidazole derivatives as potent Angiotensin II (ANG II) receptor type 1 (AT1) blockers (ARBs) has been reported in the current study. Our efforts have been directed towards the development of an efficient synthetic route allowing the facile introduction of substituents on the imidazole ring. In particular, a series of imidazole based compounds bearing the biphenyl moiety at the N - 1 position, a halogen atom at the C-4 and polar substituents such as hydroxymethyl, aldo or carboxy group at the C-2 position were designed and synthesized. These compounds were evaluated for binding to human AT1 receptor and for ANG II antagonism in vitro on isolated rat uterus. Among them, 5-butyl-1-[[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-2-carboxylic acid (30) exhibited higher binding affinity compared to the other analogues tested (-log IC50 = 8.46). The latter analogue was also found to be the most active in the rat uterotonic test (pA(2) = 7.83). Importantly, the binding affinity was higher to that of losartan (-log IC50 = 8.25) indicating the importance of carboxy group at the C-2 position. Experimental findings are in good agreement with docking studies, which were undertaken in order to investigate ligand/AT1 receptor interactions. (C) 2012 Elsevier Masson SAS. All rights reserved.
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