Synthesis of (R)-N-Arylsulfonyl-Leucylamide Derivatives as New γ-Secreatase Inhibitors

• Main Authors: Hsu,Yu-chia, 許育嘉
• Other Authors: Hu,Ming-Kuan
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/9p9r7m

碩士 === 國防醫學院 === 藥學研究所 === 104 === Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and its clinical symptoms are characterized by dysfunction in cognition and memory. The amyloid hypothesis has been known to be the targets for the potential therapies for the disease. According to this hypothesis, many therapeutic approaches in AD are focused on reducing neurotoxicity by decreasing the concentration of cerebral Aβ.Aβ is generated from sequential cleavage of amyloid precursor protein (APP) by two proteases, β-secretase and γ-secretase. Thus, inhibition of γ-secretase is one of therapeutic approaches to treat the underlying pathology of AD. There are many types of N-arylsulfonamides reported to decrease Aβ concentration by inhib iting γ-secretase. In this study, we tried to synthesize new N-arylsulfonamide derivatives based on N- (4-chlorophenylsulfonyl)- N-(2-fluorobenzyl)-leucylamide (YT6) a potent γ- secretase inhibitor. We took it as a lead compound and manipulated its structure and got a series of N-subsituted arylsulfonamide derivatives. The synthetic compounds were screened for γ-secretase inhibition by using a Gal4-tagged APP and a Gal-promoter luciferase report gene assays. Among them, compound with N-4-(dimethylamino)-3-florophenyl substituent (YT1-D2) is more active than DAPT and YT6 for the inhib ition of γ-secretase at 10 μM levels, while Notch selectivity N-4-(dimethylamino)-2-fluorobenzyl substituent (YT1-D1) is high selectivity.