有機合成の力と技でアルツハイマー病に挑む

Abstract

It is widely believed that the production and deposition of amyloid β-peptides (Aβ) play a key role in the pathogenesis of Alzheimer's disease (AD). These Aβ are generated through a sequence of proteolytic cleavages of the amyloid precursor protein (APP) by membrane-bound aspartic proteases, .β-secretase and γ-secretase. It is believed that the direct inhibition of β-and γ-secretases would reduce the production of Aβ and served as an important therapy for AD. Furthermore, in the view of the direct implication of γ-secretase in the generation of Aβ42 peptide, which has been shown to aggregate senile plaques, the γ-secretase was considered as a more important therapeutic target for the pathogenesis of AD. Thus, we started to screen potent inhibitors of γ-secretase by modification of DAPT (13) derivatives and develop a functional analysis of these inhibitors. During the course of our investigation of potential inhibitors for γ-secretases, we found that the our original synthetic methodologies (Ns-strategy and efficient immobilization of our resin 7) would enable efficient syntheses of inhibitors and photoaffinity probe molecule (28). Furthermore, our synthetic probe (28) clarified that the major direct target molecules for the DAPT (13) are PS 1 CTFs, which were discovered from the genetically investigation of familial AD. In this report, we described our synthetic methodology and its medicinal chemistry as well as chemical biology applied to for the pathogenesis of AD.