Pissarnitski Dmitri
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Curr Opin Drug Discov Devel. 2007 Jul;10(4):392-402.
Inhibition of the production of insoluble amyloid-Beta (ABeta) is a widely pursued strategy for the treatment of Alzheimer's disease (AD). The final step in the generation of ABeta from the amyloid precursor protein (APP) involves cleavage by gamma-secretase, and gamma-secretase inhibitors (GSIs) have been shown to reduce the amyloid burden in animal models of AD. Unfortunately, GSIs also cause inhibition of the cleavage of other gamma-secretase substrates, including Notch, while the co-inhibition of Notch processing by GSIs in animal studies was observed to result in a gamut of side effects. A new class of compounds, known as gamma-secretase modulators (GSMs), inhibit the amyloidogenic function of gamma-secretase without interfering in the processing of Notch and other substrates. While the exact reason for the selectivity of these agents remains unclear, they are thought to intervene at an allosteric site on gamma-secretase and cause a shift of the preferred APP cleavage site so that shorter, more soluble peptides (eg, ABeta(38)) are produced instead of the highly insoluble ABeta(42). This review describes the history of the discovery of GSMs and the current medicinal chemistry efforts aimed at providing clinically useful GSM compounds.
抑制不溶性β淀粉样蛋白（Aβ）的产生是治疗阿尔茨海默病（AD）广泛采用的策略。淀粉样前体蛋白（APP）生成Aβ的最后一步涉及γ-分泌酶的切割，γ-分泌酶抑制剂（GSIs）已被证明可减轻AD动物模型中的淀粉样蛋白负担。不幸的是，GSIs也会抑制其他γ-分泌酶底物（包括Notch）的切割，而在动物研究中观察到GSIs对Notch加工的共同抑制会导致一系列副作用。一类新型化合物，称为γ-分泌酶调节剂（GSMs），可抑制γ-分泌酶的淀粉样生成功能，而不干扰Notch和其他底物的加工。虽然这些药物具有选择性的确切原因尚不清楚，但人们认为它们作用于γ-分泌酶的变构位点，导致APP首选切割位点发生偏移，从而产生更短、更易溶的肽（例如，Aβ(38)），而不是高度不溶的Aβ(42)。本综述描述了GSMs的发现历史以及目前旨在提供具有临床应用价值的GSM化合物的药物化学研究工作。
