Abstract:
:A convenient and facile synthesis, in silico 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 IC(50) = 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 IC(50) = 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.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Agelis G,Resvani A,Durdagi S,Spyridaki K,Tůmová T,Slaninová J,Giannopoulos P,Vlahakos D,Liapakis G,Mavromoustakos T,Matsoukas Jdoi
10.1016/j.ejmech.2012.07.040subject
Has Abstractpub_date
2012-09-01 00:00:00pages
358-74eissn
0223-5234issn
1768-3254pii
S0223-5234(12)00466-7journal_volume
55pub_type
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