Benzophenone derivatives and related compounds as potent histamine H3-receptor antagonists and potential PET/SPECT ligands.
Para-substituted aromatic ethers with benzophenone or related structural elements and a 3-(1H-imidazol-4-yl)propyloxy moiety were prepared by Mitsunobu-type ether synthesis or SNAr reaction. Most of the title compounds possess high antagonist potency in histamine H3-receptor assays in vitro as well as in vivo in mouse CNS following oral administration. After defining 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl phenyl methanone as a new lead, structure-activity relationships were investigated for this new class of compounds. Substitution of the meta'-position of the benzophenone moiety with halogen atoms (e.g., iodine, fluorine) led to compounds with high antagonist potency in vitro as well as in vivo (Ki = 9.3 and 4.3 nM, ED50 = 0.7 and 0.47 mg/kg p.o., 18 and 12, respectively). A receptor profile of several functional in vitro assays for several biogenic amine receptors for the meta'-iodinated derivative demonstrated high selectivity toward the histamine H3 receptor.
Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2 + 4, 14195 Berlin, Germany.
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A
Sasse
X
X
Ligneau
B
B
Sadek
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S
Elz
H H
HH
Pertz
C R
CR
Ganellin
J M
JM
Arrang
J C
JC
Schwartz
W
W
Schunack
H
H
Stark
D000818:Animals; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed; D015899:Tomography, Emission-Computed, Single-Photon
D001577:Benzophenones; D006633:Histamine Antagonists; D008024:Ligands; D018100:Receptors, Histamine H3