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Novel histamine H-3-receptor antagonists with carbonyl- substituted 4-(3-(phenoxy)propyl)-1H-imidazole structures like ciproxifan and related compounds.
Journal of Medicinal Chemistry
3987 - 3994.
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 SNAr 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
|Title:||Novel histamine H-3-receptor antagonists with carbonyl- substituted 4-(3-(phenoxy)propyl)-1H-imidazole structures like ciproxifan and related compounds|
|Additional information:||Journal Article OCT 19 368HL Stark H Free Univ Berlin, Inst Pharmaceut, Koningin Luise Str 2&4, D-14195 Berlin, Germany J MED CHEM|
|Keywords:||absorption, Administration, AFFINITIES, affinity, antagonist, ANTAGONISTS, As, Brain, CEREBRAL-CORTEX, ciproxifan, DERIVATIVES, development, DRUG, H-3 RECEPTOR ANTAGONISTS, H-3-RECEPTOR ANTAGONIST, HIGH-AFFINITY, HIGHLY POTENT, Histamine, I-125 IODOPROXYFAN, in vitro, in vivo, In-vitro, in-vivo, LEVEL, ligands, MED, MONKEY, novel, NUMBER, Oral, Other, plasma, PRESYNAPTIC H-3-RECEPTORS, RANGE, Receptor, screening, SELECTIVITY, Structure, SUBTYPES, TELE- METHYLHISTAMINE|
|UCL classification:||UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry|
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