Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Curr Alzheimer Res. 2010 May;7(3):207-9. doi: 10.2174/156720510791050920.
Overwhelming evidence supports a central role for the amyloid beta-peptide (Abeta) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce Abeta from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting gamma-secretase, which generates the C-terminus of Abeta; however, gamma-secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter gamma-secretase activity to reduce Abeta production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that gamma-secretase can be selectively inhibited in this way by naphthyl-substituted gamma-aminoketones and gamma-aminoalcohols. These early hits, however, suffered from chemical instability and/or poor potency. Iterative design, synthesis and evaluation have led to the discovery of Notch-sparing gamma-secretase inhibitors with substantially increased potencies in biochemical and cellular assays. These compounds are of low molecular weight and are under evaluation for drug-like properties. The discovery and development of these compounds will be discussed.
大量证据支持淀粉样β肽（Aβ）在阿尔茨海默病（AD）发病机制中的核心作用，而产生 Aβ的前体蛋白 APP 的蛋白酶是治疗干预的主要靶点。人们已经投入了相当大的精力来靶向γ-分泌酶，它产生 Aβ的 C 末端；然而，γ-分泌酶抑制剂由于干扰 Notch 信号通路而引起严重的毒性。我们一直在致力于开发直接改变γ-分泌酶活性的化合物，以减少 Aβ的产生，而不影响 Notch 的蛋白水解。使用纯化的酶和底物，我们已经表明，γ-分泌酶可以通过萘基取代的γ-氨基酮和γ-氨基醇以这种方式被选择性抑制。然而，这些早期的命中化合物由于化学不稳定性和/或效力差而受到影响。经过反复的设计、合成和评估，发现了 Notch 保留的γ-分泌酶抑制剂，它们在生化和细胞测定中的效力大大提高。这些化合物具有低分子量，正在评估其作为药物的特性。将讨论这些化合物的发现和开发。
