Synthesis, Potency, and In Vivo Profiles of Quinoline Containing Histamine H3 Receptor Inverse Agonists

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• 作者：Robert J. Altenbach ; Huaqing Liu ; Patricia N. Banfor ; Kaitlin E. Browman ; Gerard B. Fox ; Ryan M. Fryer ; Victoria A. Komater ; Kathleen M. Krueger ; Kennan Marsh ; Thomas R. Miller ; Jia Bao Pan ; Liping Pa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 1, 2007
• 年：2007
• 卷：50
• 期：22
• 页码：5439 - 5448
• 全文大小：168K
• 年卷期：v.50,no.22(November 1, 2007)
• ISSN：1520-4804

文摘

A new structural series of histamine H₃ receptor antagonist was developed. The new compounds are basedon a quinoline core, appended with a required basic aminoethyl moiety, and with potency- and property-modulating heterocyclic substituents. The analogs have nanomolar and subnanomolar potency for the ratand human H₃R in various in vitro assays, including radioligand competition binding as well as functionaltests of H₃ receptor-mediated calcium mobilization and GTPS binding. The compounds possessed favorabledrug-like properties, such as good PK, CNS penetration, and moderate protein binding across species. Severalcompounds were found to be efficacious in animal behavioral models of cognition and attention. Furtherstudies on the pharmaceutic properties of this series of quinolines discovered a potential problem with photochemical instability, an issue which contributed to the discontinuation of this series from further development.