期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 70, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2022.116917
关键词
Alzheimer's disease; 5-HT(6 )antagonists; Idalopirdine; Difluoromethyl
资金
- Foundation and Applied Basic Research Fund of Guangdong Province [2019A1515110957]
- KeyResearch and Development Program of Guangdong Province [2019B02021002]
In this study, a series of novel 1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)-1H-indole derivatives were designed and synthesized via a hybridization strategy. The optimal compound C14 showed significantly increased affinity for 5-HT6R compared to idalopirdine, along with good pharmacokinetic and in vitro metabolic properties. Furthermore, C14 efficiently reversed scopolamine induced memory deficits in rats, suggesting its potential as a cognition-enhancing agent.
Herein, a series of novel 1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)-1H-indole derivatives were designed and synthesized via hybridization strategy of idalopirdine and SB-271046. The optimal compound C14 (K-i = 0.085 nM), with difluoromethyl on C3 position on indole scaffold, increased the affinity for the 5-HT6R up to 10 -folds than idalopirdine (K-i = 0.83 nM). Additionally, C14 had good pharmacokinetic properties and in vitro metabolic properties. Finally, C14 could efficiently reverse the scopolamine induced emotional memory deficits in novel object recognition assay in rats. Thus, we propose C14 might be considered as a new cognition -enhancing agent and the further studies are now underway in our laboratory.
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