Synthesis, potency, and in vivo profiles of quinoline containing histamine H3 receptor inverse agonists

被引：32

作者：

Altenbach, Robert J. ^{[1
]}

Liu, Huaqing ^{[1
]}

Banfor, Patricia N. ^{[1
]}

Brownian, Kaitlin E. ^{[1
]}

Fox, Gerard B. ^{[1
]}

Fryer, Ryan M. ^{[1
]}

Komater, Victoria A. ^{[1
]}

Krueger, Kathleen M. ^{[1
]}

Marsh, Kennan ^{[1
]}

Miller, Thomas R. ^{[1
]}

Pan, Jia Bao ^{[1
]}

Pan, Liping ^{[1
]}

Sun, Minghua ^{[1
]}

Thiffault, Christine ^{[1
]}

Wetter, Jill ^{[1
]}

Zhao, Chen ^{[1
]}

Zhou, Deliang ^{[1
]}

Esbenshade, Timothy A. ^{[1
]}

Hancock, Arthur A. ^{[1
]}

Cowart, Marlon D. ^{[1
]}

机构：

[1] Abbott Labs, Dept R4MN, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 22期

关键词：

D O I：

10.1021/jm0705051

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new structural series of histamine H-3 receptor antagonist was developed. The new compounds are based on 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 rat and human H3R in various in vitro assays, including radioligand competition binding as well as functional tests of H-3 receptor-mediated calcium mobilization and GTP gamma S binding. The compounds possessed favorable drug-like properties, such as good PK, CNS penetration, and moderate protein binding across species. Several compounds were found to be efficacious in animal behavioral models of cognition and attention. Further studies 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.

引用

页码：5439 / 5448

页数：10

共 60 条

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