Novel histamine H(3)-receptor antagonists with carbonyl-substituted 4-(3-(phenoxy)propyl)-1H-imidazole structures like ciproxifan and related compounds.
Novel histamine H(3)-receptor antagonists possessing a 4-(3-(phenoxy)propyl)-1H-imidazole structure generally substituted in the para-position of the phenyl ring have been synthesized according to Mitsunobu or S(N)Ar reactions. With in vitro and in vivo screening for H(3)-receptor antagonist potency, the carbonyl-substituted derivatives proved to be highly active compounds. A number of compounds showed in vitro affinities in the subnanomolar concentration range, and the 4-hexanoyl (10) and 4-acetyl-3-methyl (29) substituted derivatives showed in vivo antagonist potencies of about 0.1 mg/kg after po administration. Many proxifans were also tested for their affinities at other histamine receptor subtypes thereby demonstrating their pronounced H(3)-receptor subtype selectivity. Since the cyclopropyl ketone derivative 14 (ciproxifan) had high affinity in vitro as well as high potency in vivo, it was selected for further studies in monkeys. It showed good oral absorption and long-lasting, dose-dependent plasma levels making it a promising compound for drug development.
Stark
H
H
Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany. stark@schunet.pharmazie.fuberlin.de
Sadek
B
B
Krause
M
M
Hüls
A
A
Ligneau
X
X
Ganellin
C R
CR
Arrang
J M
JM
Schwartz
J C
JC
Schunack
W
W
D000818:Animals; D016275:Atrial Function; D002540:Cerebral Cortex / Q000378:metabolism / Q000648:ultrastructure; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D000882:Haplorhini; D006325:Heart Atria / Q000187:drug effects; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000502:physiology; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000502:physiology; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
D006633:Histamine Antagonists; D007093:Imidazoles; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; C115705:ciproxifan