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Benzophenone Derivatives and Related Compounds as Potent Histamine H 3 ‐Receptor Antagonists and Potential PET/SPECT Ligands
Author(s) -
Sasse Astrid,
Ligneau Xavier,
Sadek Bassem,
Elz Sigurd,
Pertz Heinz H.,
Ganellin C. Robin,
Arrang JeanMichel,
Schwartz JeanCharles,
Schunack Walter,
Stark Holger
Publication year - 2001
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 - 10.1002/1521-4184(200102)334:2<45::aid-ardp45>3.0.co;2-2
Subject(s) - chemistry , benzophenone , moiety , in vivo , histamine , stereochemistry , ether , pharmacology , organic chemistry , medicine , biology , microbiology and biotechnology
Para ‐substituted aromatic ethers with benzophenone or related structural elements and a 3‐(1 H ‐imidazol‐4‐yl)propyloxy moiety were prepared by Mitsunobu‐type ether synthesis or S N Ar reaction. Most of the title compounds possess high antagonist potency in histamine H 3 ‐receptor assays in vitro as well as in vivo in mouse CNS following oral administration. After defining 4‐(3‐(1 H ‐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 (K i = 9.3 and 4.3 nM, ED 50 = 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 H 3 receptor.