Design, Synthesis, and Structure鈥揂ctivity Relationship of N-Arylnaphthylamine Derivatives as Amyloid Aggregation Inhibitors

详细信息    查看全文

• 作者：Roberto Di Santo ; Roberta Costi ; Giuliana Cuzzucoli Crucitti ; Luca Pescatori ; Federica Rosi ; Luigi Scipione ; Diana Celona ; Mario Vertechy ; Orlando Ghirardi ; Paola Piovesan ; Mauro Marzi ; Silvio Caccia ; Giovanna Guiso ; Fabrizio Giorgi ; Patrizia Minetti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8538-8548
• 全文大小：436K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

Dyes like CR are able to inhibit the aggregation of A尾 fibrils. Thus, a screening of a series of dyes including ABBB (1) was performed. Its main component 2 tested in an in vitro assay (i.e., ThT assay) showed good potency at inhibiting fibrils association. Congeners 4鈥?b>9 have been designed and synthesized as inhibitors of A尾 aggregation. A number of these newly synthesized compounds have been found to be active in the ThT assay with IC₅₀ of 1鈥?7.4 渭M. The most potent compound of this series, 4k, showed micromolar activity in this test. Another potent derivative 4q (IC₅₀ = 5.6 渭M) rapidly crossed the blood鈥揵rain barrier, achieving whole brain concentrations higher than in plasma. So 4q could be developed to find novel potent antiaggregating 尾A agents useful in Alzheimer disease as well as other neurological diseases characterized by deposits of amyloid aggregates.