Discovery and optimization of Lu AF58801, a novel, selective and brain penetrant positive allosteric modulator of alpha-7 nicotinic acetylcholine receptors: Attenuation of subchronic phencyclidine (PCP)-induced cognitive deficits in rats following oral administration
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- 作者：J酶rgen Eskildsen ; John P. Redrobe ; Anette G. Sams ; Kim Dekermendjian ; Morten Laursen ; Jette B. Boll ; Roger L. Papke ; Christoffer Bundgaard ; Kristen Frederiksen ; Jesper F. Bastlund
- 关键词：Nicotinic acetylcholine receptors ; Positive allosteric modulator ; Electrophysiology ; Lead optimization ; Novel object recognition
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：1 January, 2014
- 年：2014
- 卷：24
- 期：1
- 页码：288-293
- 全文大小：1628 K
文摘
In this Letter, we describe a chemical lead optimization campaign starting from a novel, weak 伪7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) hit from a HTS screen. Exploration of the structure-activity relationships for 伪7 PAM potency, intrinsic hepatic clearance, the structure-property relationships for lipophilicity, and thermodynamic solubility, led to the identification of Lu AF58801: a potent, orally available, brain penetrant PAM of the 伪7 nicotinic acetylcholine receptor, showing efficacy in a novel object recognition task in rats treated subchronically with phencyclidine (PCP).