Synthesis and Pharmacological Evaluation of N-Substituted Arylsulfonamide Derivatives asNew γ-Secretase Inhibitors

• Main Authors: Chen, Chia-Yu, 陳佳瑜
• Other Authors: Hu, Ming-Kuan
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/00797993498231743572

碩士 === 國防醫學院 === 藥學研究所 === 99 === Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease characterized by beta-amyloid (Aβ) deposition and neurofibrillary tangles (NFTs) formation. The overproduction and accumulation of Aβ are key pathogenic events in AD progression. Aβ is generated from proteolytic cleavage of amyloid precursor protein (APP) sequentially by β- and γ-secretases, whereas NFTs observed intracellularly are a result of the aggregation of hyperphosphorylated tau. Therefore, γ-secretase inhibition has been and remains an active field of drug discovery for AD. Some arylsulfones have been reported to be selective, potent γ-secretase inhibitors. One of them is GSI-953 (begacestat), which is actually a hexafluorovalinol derivative. Aiming at developing new molecules for AD therapies, we took it as a lead compound and manipulated its structure to provide a series of N-substituted arylsulfonamide derivatives. These synthetic arylsulfonamides were screened by using a Gal4-tagged APP and a Gal4-promotor luciferase reporter gene assays to moniter the inhibitory potencies against γ-secretase activity. Among them, only compounds C6-7 (IC50 = 8.7 μM) and C5-5g (IC50 = 11.7 μM) showed moderate potencies with 59% and 42% inhibitions of γ-secretase activity, respectively, at 10 μM levels.