新型γ-分泌酶调节剂SPI-1865的研发历程概述

An overview in research and development process of a novel γ-secretase modulator SPI-1865

阿尔茨海默症(Alzheimer's disease,AD)为进行性的神经退行性疾病,目前缺乏有效的治疗手段。β淀粉样蛋白(β-amyloid,Aβ)在脑神经细胞外过度沉积形成的寡聚体和淀粉样斑块与阿尔茨海默症的发生、发展密切相关。γ-分泌酶是β淀粉样蛋白代谢过程中的关键酶,为研发阿尔茨海默症治疗药物的关键靶点。针对此靶点研发的γ-分泌酶调节剂(γ-secretase modulators,GSM)因对Notch等蛋白影响较小,有广阔的应用前景。本文总结了源于黑升麻(Black cohosh,Cimicifuga racemosa)的环阿尔廷型三萜为先导物的结构优化历程,最终获得γ-分泌酶调节剂药物候选物SPI-1865,以期为γ-分泌酶调节剂的开发与改造提供有价值的参考。

Alzheimer’s disease is a progressive neurodegenerative disorder,which is lack of efficient treatment measures.The β-amyloid （Aβ） oligomers and senile plaques,which are the result of β-amyloid aggregation outside the brain neurons,are strongly implicated the pathogenesis of AD.γ-Secretase,a key enzyme involved in generation of Aβ,is a potential target in the development of drugs for AD therapy.γ-Secretase modulators are highly selective and have broad application prospects.This article briefly reviewed the development process of a novel γ-Secretase modulator SPI-1865,aiming at providing valuable information for development and structural modifications of related GSM.