Development of FUB 181, a Selective Histamine H 3 -Receptor Antagonist of High Oral in Vivo Potency with 4-(ω-(Arylalkyloxy)alkyl)-1H-imidazole Structure ✩ 1) Holger Stark a) *, Annette Hüls a) , Xavier Ligneau b) , Katja Purand a) , Heinz Pertz a) , Jean-Michel Arrang c) , Jean-Charles Schwartz c) , and Walter Schunack a) a) Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany b) Laboratoire Bioprojet, 30 rue des Francs-Bourgeois, F-75003 Paris, France c) Unité de Neurobiologie et Pharmacologie Moléculaire, Centre Paul Broca de l’INSERM (U109), 2ter rue d’Alésia, F-75014 Paris, France Key Words: Histamine H3 receptor; antagonist; FUB 181; imidazolylpropyl ether Summary Introduction During the last decade several synthetic attempts have been carried out by various laboratories [1–5] to develop potent and selective antagonists of the histamine H 3 -receptor subtype first described by Arrang et al. in 1983 [6] . Potent and selective antagonists are necessary to characterize the pharmacological and physiological functions of this receptor subtype. At pre- sent, histamine H 3 receptors have been identified as autore- ceptors located presynaptically on the axon terminals of histaminergic neurones controlling histamine release and synthesis by a negative feed-back mechanism [6] . In addition, H 3 receptors have been found as heteroreceptors located on non-histaminergic neurones in the central nervous system (CNS) [7] and on sympathetic, parasympathetic, and non-ad- renergic non-cholinergic nerve fibres supplying the gastroin- testinal [8] , bronchial [9] , and cardiovascular system [10] , thus modulating the effect on a number of different neurotransmit- ters [11–15] . H 3 receptors may also be located on endocrine cells, e.g., enterochromaffin and enterochromaffin-like cells [16, 17] . Their activation causes inhibition of release of the respective mediators. Histamine H 3 -receptor antagonists have not yet been used clinically, but several therapeutic indications for H 3 -receptor antagonists have been pro- posed [17–19] , e.g., various diseases or conditions of the CNS like memory and learning deficits [20, 21] , cognitive and sleep disorders [22] , and epilepsy [23] . The common structural features of different developments in the field of highly potent antagonists led to a general construction pattern for histamine H 3 -receptor antago- nists [18] . A nitrogen-containing heterocycle connected with a polar group via an alkyl chain seems to be of fundamental importance for H 3 -receptor antagonist activity. H 3 -receptor potency can be further increased by the introduction of a lipophilic portion linked with the polar group via an addi- tional alkyl spacer. Although some non-imidazoles such as betahistine [24] , dimaprit [25] , and clozapine [26] have some antagonist potency, replacement of or variation on the imid- azole ring to other nitrogen-containing ring systems were generally accompanied by a dramatic loss of potency [27, 28] . On the other hand, various functional groups are tolerated as polar groups without a decrease in H 3 -receptor antagonist potency. Thus, different compounds such as amides [29] , isothiourea [4, 30] , guanidines [31] , esters [32] , carbamates [32, 33] , and oxadi-azoles [34] are suitable antagonists for H 3 -re- ceptors (for review see Leurs et al. [19] , Stark et al. [17] ). Since the reference antagonist thioperamide and the highly active compound clobenpropit showed some affinity for 5-HT 3 receptors, new leads were recommended for the evaluation of H 3 -receptor mediated functions [35] . In previous studies, ben- Arch. Pharm. Pharm. Med. Chem. © WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998 0365-6233/98/0606/0211 $17.50 +.50/0 ——— 1) Presented in parts: XXIIIrd Annual Meeting of the European Histamine Research Society (EHRS) (Abstract p. 120), Budapest, Hungary, May 18–21, 1994; XIIIth International Symposium on Medicinal Chemistry (Abstract P134), Paris, France, September 19–23, 1994; 2nd European Congress of Pharmaceutical Sciences (Free Communication FC22 [42] , poster P84 [52] ), Berlin, September 29–October 1, 1994; VIIth Noordwijkerhout-Camerino Symposium, Trends in Drug Research (Abstract P20), Noordwijkerhout, The Netherlands, May 15–19, 1997. A series of 4-(ω-(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 τ - 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 antagonist activity. Addition- ally, 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 exhib- ited low activity at adrenergic α1, β1/2, 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. Development of FUB 181 211