TY - JOUR
T1 - Progress in the proxifan class
T2 - heterocyclic congeners as novel potent and selective histamine H3-receptor antagonists
AU - Graßmann, Sven
AU - Sadek, Bassem
AU - Ligneau, Xavier
AU - Elz, Sigurd
AU - Ganellin, C. Robin
AU - Arrang, Jean Michel
AU - Schwartz, Jean Charles
AU - Stark, Holger
AU - Schunack, Walter
N1 - Funding Information:
The contribution of Inge Walther to some pharmacological experiments is greatly appreciated. This work was supported by the Biomedical & Health Research Programme (BIOMED) of the European Union and the Fonds der Chemischen Industrie, Verband der Chemischen Industrie, Frankfurt/Main, Germany.
PY - 2002
Y1 - 2002
N2 - Histamine H3 receptors are critically involved in the pathophysiology of several disorders of the central nervous system (CNS). Among other families of H3-receptor ligands, the proxifan class has recently been described to contain numerous potent histamine H3-receptor antagonists, e.g. ciproxifan or imoproxifan. In the present study, we report on the design of novel heterocyclic proxifan analogues and their antagonist potencies at histamine H3 receptors. The new compounds were tested for in vitro and in vivo H3-receptor antagonist potencies in different species as well as for H3-receptor selectivity vs. H1 and H2 receptors. In vitro, all compounds investigated proved to be potent H3-receptor antagonists in the rat as well as in the guinea-pig. In addition, they showed good to high oral CNS potency in vivo in mice. Especially, oxadiazole derivatives 24-26 displayed nanomolar antagonist activity in vitro and high potency in vivo (ED50=0.47-0.57 mg/kg). The results show that the additional heteroaromatic moieties might act as bioisosteres of the ketone or oxime moieties of ciproxifan or imoproxifan, respectively, and might cause divergent pharmacokinetic properties. Thus, these novel H3-receptor antagonists are interesting leads for further development.
AB - Histamine H3 receptors are critically involved in the pathophysiology of several disorders of the central nervous system (CNS). Among other families of H3-receptor ligands, the proxifan class has recently been described to contain numerous potent histamine H3-receptor antagonists, e.g. ciproxifan or imoproxifan. In the present study, we report on the design of novel heterocyclic proxifan analogues and their antagonist potencies at histamine H3 receptors. The new compounds were tested for in vitro and in vivo H3-receptor antagonist potencies in different species as well as for H3-receptor selectivity vs. H1 and H2 receptors. In vitro, all compounds investigated proved to be potent H3-receptor antagonists in the rat as well as in the guinea-pig. In addition, they showed good to high oral CNS potency in vivo in mice. Especially, oxadiazole derivatives 24-26 displayed nanomolar antagonist activity in vitro and high potency in vivo (ED50=0.47-0.57 mg/kg). The results show that the additional heteroaromatic moieties might act as bioisosteres of the ketone or oxime moieties of ciproxifan or imoproxifan, respectively, and might cause divergent pharmacokinetic properties. Thus, these novel H3-receptor antagonists are interesting leads for further development.
KW - Antagonist
KW - Ciproxifan
KW - H receptor
KW - Histamine
KW - Imoproxifan
KW - Proxifan
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U2 - 10.1016/S0928-0987(02)00024-6
DO - 10.1016/S0928-0987(02)00024-6
M3 - Article
C2 - 11988398
AN - SCOPUS:0036225128
SN - 0928-0987
VL - 15
SP - 367
EP - 378
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
IS - 4
ER -