Synthesis and Biological Evaluation of Analogues of a Novel Inhibitor of β-Amyloid Secretion

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• 作者：Enakshi Chakrabarti ; Subrata Ghosh ; Sushabhan Sadhukhan ; Lawrence Sayre ; Gregory P. Tochtrop ; Jonathan D. Smith
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：July 22, 2010
• 年：2010
• 卷：53
• 期：14
• 页码：5302-5319
• 全文大小：1232K
• 年卷期：v.53,no.14(July 22, 2010)
• ISSN：1520-4804

文摘

A drug library of 17200 compounds was screened to select small molecules that inhibit the secretion of amyloid β peptide (Aβ), the major component of Alzheimer disease senile plaques, from a human neuronal cell line. Twenty-nine hits were validated that decreased Aβ secretion by >40% at 10 μM, for a 0.17% hit rate. A lead hit was selected for further study based on its activity and low cytotoxicity, and it was found to inhibit Aβ secretion through activation of the α-secretase pathway. Twenty-four commercially available and 53 synthesized analogues were analyzed for activity. Selected analogues were evaluated for biological stability by incubation with hepatoma cells and for transcellular permeability using Caco-2 cell monolayers. The analogue with the best permeability was evaluated in 2-month old amyloid precursor protein transgenic mice and found to acutely reduce cerebral Aβ levels by 40% after a single iv administration.