Novel Alpha-7 Nicotinic Acetylcholine Receptor Agonists Containing a Urea Moiety: Identification and Characterization of the Potent, Selective, and Orally Efficacious Agonist 1-[6-(4-Fluorophenyl)pyri
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- 作者：Chiara Ghiron ; Simon N. Haydar ; Suzan Aschmies ; Hendrick Bothmann ; Cristiana Castaldo ; Giuseppe Cocconcelli ; Thomas A. Comery ; Li Di ; John Dunlop ; Tim Lock ; Angela Kramer ; Dianne Kowal ; Flora Jow ; Ste
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：June 10, 2010
- 年：2010
- 卷：53
- 期：11
- 页码：4379-4389
- 全文大小：955K
- 年卷期：v.53,no.11(June 10, 2010)
- ISSN：1520-4804
文摘
Alpha-7 nicotinic acetylcholine receptor (α7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4−18) of the α7 nAChR deriving from our continuing efforts in the areas of Alzheimer’s disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the α7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.