Development of FUB 181, a selective histamine H3-receptor antagonist of high oral in vivo potency with 4-(omega-(arylalkyloxy)alkyl)-1H-imidazole structure.

A series of 4-(omega-(arylalkyloxy)alkyl)-1H-imidazoles and related sulphur-containing compounds have been prepared and evaluated for their histamine H3-autoreceptor antagonist in vitro potency in an assay on synaptosomes of rat cerebral cortex. In addition, the in vivo potency has been determined from the changes in N tau-methylhistamine levels in brain after p.o. administration to mice. Compounds with different alkyl chains and various aryl moities have been synthesized and tested to explore structure-activity relationships. Within this series of novel antagonists, (1H-imid-azol-4-yl)methyl and 2-(1H-imidazol-4-yl)ethyl ether derivatives showed low to moderate H3-receptor antagonist potency, whereas the corresponding allyl and propyl derivatives were compounds with high antagonist in vitro potency. Corresponding thioether or sulphoxide derivatives also showed antagonists 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 ED50 values of 0.76 and 0.80 mg/kg, respectively. On the other hand, all compounds tested showed weak activity at histamine H1 or H2 receptors. Furthermore, the most promising ether FUB 181 exhibited low activity at adrenergic alpha 1, beta 1/2, serotonergic 5-HT2A, 5-HT3, and muscarinic M3 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 H3 receptors potently and selectively.