Sasse A, Ligneau X, Sadek B, Elz S, Pertz H H, Ganellin C R, Arrang J M, Schwartz J C, Schunack W, Stark H
Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2 + 4, 14195 Berlin, Germany.
Arch Pharm (Weinheim). 2001 Feb;334(2):45-52. doi: 10.1002/1521-4184(200102)334:2<45::aid-ardp45>3.0.co;2-2.
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.
通过光延型醚合成或亲核芳香取代反应制备了具有二苯甲酮或相关结构单元以及3-(1H-咪唑-4-基)丙氧基部分的对位取代芳香醚。大多数标题化合物在体外组胺H3受体测定中以及口服给药后在小鼠中枢神经系统体内均具有高拮抗剂活性。在将4-(3-(1H-咪唑-4-基)丙氧基)苯基苯基甲酮定义为新的先导化合物后，研究了这类新化合物的构效关系。用卤原子（如碘、氟）取代二苯甲酮部分的间位'位置，得到了在体外和体内均具有高拮抗剂活性的化合物（Ki分别为9.3和4.3 nM，ED50分别为0.7和0.47 mg/kg口服，分别为18和12）。对间位碘代衍生物的几种生物胺受体的几种功能性体外测定的受体谱表明对组胺H3受体具有高选择性。
