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 (Ki 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; Ki = 12 nM, ED50 = 0.54 mg/kg) and 4-[3-[4-(trifluoromethyl)-phenoxy]propyl]-1H-imidazole (10c, UCL 1409; Ki = 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 Ki + 0.20 (r = 0.78).
Ganellin
C R
CR
Department of Chemistry, Christopher Ingold Laboratories, University College London, UK.
Fkyerat
A
A
Bang-Andersen
B
B
Athmani
S
S
Tertiuk
W
W
Garbarg
M
M
Ligneau
X
X
Schwartz
J C
JC
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008761:Methylhistamines / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013574:Synaptosomes / Q000378:metabolism
C101619:4-(3-(4-(trifluoromethyl)phenoxy)propyl)-1H-imidazole; C101618:4-(3-(4-cyanophenoxy)propyl)-1H-imidazole; D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D018100:Receptors, Histamine H3; C020404:tele-methylhistamine; D011188:Potassium