Pyrazoles as potential histamine H3-receptor antagonists.
In search of structure-activity relationships among histamine H3-receptor antagonists, the imidazole ring of known H3-receptor antagonists was replaced by different heteroaromatic ring systems. Thus, pyrazoles with ether (4,5) and carbamate (6,7) moieties as functional groups were synthesized. Reaction of the hydrochloride of 4-(3-hydroxypropyl)pyrazole (1) with phenyl or benzyl isocyanates mainly gave the carbamates 6 and 7, whereas a similar reaction with 1 as the free base furnished the N-carbamoylpyrazoles 8 and 9. The bifunctional pyrazoles 10 and 11 were formed as by-products. The compounds obtained did not show significant H3-receptor antagonist activity in vitro (rat brain cortex) or in vivo (mouse brain). These results demonstrate the importance of the imidazole moiety for H3-receptor antagonists. The new compounds were also screened for H1-receptor antagonist activity on the isolated guinea-pig ileum and for H2-receptor antagonist activity on the isolated spontaneously beating guinea-pig right atrium. The substances showed only weak antagonistic activity at both histamine receptors H1 and H2.
Kieć-Kononowicz
K
K
Department of Chemical Technology of Drugs, Collegium Medicum, Jagiellonian University, Kraków, Poland.
Ligneau
X
X
Schwartz
J C
JC
Schunack
W
W
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006633:Histamine Antagonists; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats
D006633:Histamine Antagonists; D011720:Pyrazoles