Premium
Development of FUB 181, a Selective Histamine H 3 ‐Receptor Antagonist of High Oral in Vivo Potency with 4‐(?gv‐(Arylalkyloxy)alkyl)‐1 H ‐imidazole Structure
Author(s) -
Stark Holger,
Hüls Annette,
Ligneau Xavier,
Purand Katja,
Pertz Heinz,
Arrang JeanMichel,
Schwartz JeanCharles,
Schunack Walter
Publication year - 1998
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(199806)331:6<211::aid-ardp211>3.0.co;2-p
Subject(s) - chemistry , potency , in vivo , antagonist , stereochemistry , histamine , histamine h3 receptor , ether , histamine h1 receptor , receptor , pharmacology , in vitro , biochemistry , biology , organic chemistry , microbiology and biotechnology
A series of 4‐(?gv‐(arylalkyloxy)alkyl)‐1 H ‐imidazoles and related sulphur‐containing compounds have been prepared and evaluated for their histamine H 3 ‐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, (1 H ‐imidazol‐4‐yl)methyl and 2‐(1 H ‐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 vitro 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)‐1 H ‐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 α 1 , β 1/2 , serotonergic 5‐HT 2A , 5‐HAT 3 , 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.