Development of FUB 181, a Selective Histamine H3-Receptor Antagonist of High Oralin Vivo Potency with 4-(?gv-(Arylalkyloxy)alkyl)-1H-imidazole Structure

A series of 4-(ω-taryialkyloxy)alkyl)-1H-imidazoles, and related sulphur-containing compounds have been prepared and evaluated for their histamine H 3 -autoreceptor antagonist in vuro potency in an assay on synaptosomes of rat cerebral cortex. in addition, the in vivo potency has been determined from the changes in N τ -methylhistamine levels in brain after p.o. administration to mice. Compounds with different alkyl chains and various aryl moities nave been synthesized and tested to explore structure-activity relationships. Within this series of novei antagonists, (1H-imidazol-4-yl)methyl and 2-(1H-imidazol-4-yl)ethyl ether derivatives showed low to moderate H 3 -receptor antagonist potency, whereas the corresponding allyl and propyl derivatives were compounds with high antagonist in vivo potency. Corresponding thioether or sulphoxide derivatives also showed antagonist activity. Additionally, some ether derivatives possessed high in vivo potency as well. The most active ether derivatives under in vivo conditions were 4- 3-(3-(4-fluorophenyl)propyloxy)propyl)-1H-imidazole (11b) and the corresponding chloro compound 11c (FUB 181) with ED 50 values of 0.76 and 0.80 mg/kg, respectively. On the other hand, all compounds tested showed weak activity at histamine H 1 or H 2 receptors. Furthermore, the most promising ether FUB 181 exhibited low activity at adrenergic μ 1 , β 1/2 , serotonergic 5-HT 2A , 5-HT; and muscarinic M 3 receptors. Time-course investigations of FUB 181 in mice showed a rapid mode of action with the highest value 3 h after p.o. application. Thus, FUB 181 appears to block histamine H 3 receptors potently and selectively.