A Novel Series of (Phenoxyalkyl)imidazoles as Potent H3-Receptor Histamine Antagonists

[[(4-Nitrophenyl)X]alkyl]imidazole isosteres (where X = NH, S, CH2S, O) of previously described [[(5-nitropyrid-2-yl)X]ethyl]imidazoles (where X = NH, S) have been synthesized and evaluated for H3-receptor histamine antagonism in vitro (K i for [3H]histamine release from rat cerebral cortex synaptos...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1996-09, Vol.39 (19), p.3806-3813
Main Authors: Ganellin, C. Robin, Fkyerat, Abdellatif, Bang-Andersen, Benny, Athmani, Salah, Tertiuk, Wasyl, Garbarg, Monique, Ligneau, Xavier, Schwartz, Jean-Charles
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Brain - drug effects
Brain - metabolism
Cerebral Cortex - secretion
Histamine Antagonists - chemical synthesis
Histamine Antagonists - pharmacology
Histamine Release - drug effects
Imidazoles - chemical synthesis
Imidazoles - pharmacology
In Vitro Techniques
Medical sciences
Methylhistamines - metabolism
Mice
Miscellaneous
Molecular Structure
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Potassium - pharmacology
Rats
Receptors, Histamine H3 - drug effects
Synaptosomes - secretion
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Summary:[[(4-Nitrophenyl)X]alkyl]imidazole isosteres (where X = NH, S, CH2S, O) of previously described [[(5-nitropyrid-2-yl)X]ethyl]imidazoles (where X = NH, S) have been synthesized and evaluated for H3-receptor histamine antagonism in vitro (K i for [3H]histamine release from rat cerebral cortex synaptosomes) and in vivo (ED50 per os in mice on brain tele-methylhistamine levels). Encouraging results led to the synthesis and testing of a novel series of substituted (phenoxyethyl)- and (phenoxypropyl)imidazoles. From the latter, 4-[3-(4-cyanophenoxy)propyl]-1H-imidazole (10a, UCL 1390; K i = 12 nM, ED50 = 0.54 mg/kg) and 4-[3-[4-(trifluoromethyl)phenoxy]propyl]-1H-imidazole (10c, UCL 1409; K i = 14 nM, ED50 = 0.60 mg/kg) have been selected as potential candidates for drug development. For 16 [(aryloxy)ethyl]imidazoles the relationship between in vitro and in vivo potency is described by the equation log ED50 = 0.47 log K i + 0.20 (r = 0.78).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm960138l