期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 214, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113189
关键词
Nicotinic alpha 7 receptor; Positive allosteric modulator; Scaffold hopping; Structure activity relationship; Cognitive improvement
资金
- Gedeon Richter Plc., Hungary
- Orion Corporation, Finland
The paper describes the discovery of a novel nicotinic alpha 7 receptor positive modulator through scaffold hopping, leading to the identification of a promising new chemotype with good physicochemical and in vitro parameters. These compounds showed favorable characteristics in vitro and in vivo evaluations, suggesting the potential to improve cognitive performance.
The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (alpha 7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized. A promising, pyrazole-containing new chemotype with good physicochemical and in vitro parameters was identified. Retrospective analysis based on homology modeling was also carried out. Besides its favorable in vitro characteristics, the most advanced derivative 69 also showed in vivo efficacy in a rodent model of cognition (scopolamine-induced amnesia in the mouse place recognition test) and acceptable pharmacokinetic properties. Based on the in vivo data, the resulting molecule with advanced drug-like characteristics has the possibility to improve cognitive performance in a biologically relevant dose range, further strengthening the view of the supportive role of alpha 7 nACh receptors in the cognitive processes. (C) 2021 Elsevier Masson SAS. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据