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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960138l

[[(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).