Findeis Mark A, Schroeder Frank C, Creaser Steffen P, McKee Timothy D, Xia Weiming
Aria Neurosciences, Incorporated, 295 Washington Ave, Suite 4N, Hamden, CT 06518, USA.
Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, 533 Tower Road, Ithaca, NY 14853-1801, USA.
Medicines (Basel). 2015 Jun 30;2(3):127-140. doi: 10.3390/medicines2030127.
Alzheimer's disease is characterized by pathogenic oligomerization, aggregation, and deposition of amyloid beta peptide (Aβ), resulting in severe neuronal toxicity and associated cognitive dysfunction. In particular, increases in the absolute or relative level of the major long form of Aβ, Aβ42, are associated with increased cellular toxicity and rapidity of disease progression. As a result of this observation, screening to identify potential drugs to reduce the level of Aβ42 have been undertaken by way of modulating the proteolytic activity of the gamma secretase complex without compromising its action on other essential substrates such as Notch. In this review we summarize results from a program that sought to develop such gamma secretase modulators based on novel natural products identified in the extract of the well-known botanical black cohosh. Following isolation of compound (SPI-014), an extensive medicinal chemistry effort was undertaken to define the SAR of and related semisynthetic compounds. Major metabolic and physicochemical liabilities in were overcome including replacement of both the sugar and acetate moieties with more stable alternatives that improved drug-like properties and resulted in development candidate (SPI-1865). Unanticipated off-target adrenal toxicity, however, precluded advancement of this series of compounds into clinical development.
阿尔茨海默病的特征是淀粉样β肽（Aβ）发生致病性寡聚化、聚集和沉积，导致严重的神经元毒性及相关认知功能障碍。特别是，主要的长形式Aβ即Aβ42的绝对或相对水平升高，与细胞毒性增加和疾病进展速度加快有关。基于这一观察结果，人们通过调节γ-分泌酶复合物的蛋白水解活性来筛选潜在药物，以降低Aβ42的水平，同时又不影响其对其他重要底物（如Notch）的作用。在这篇综述中，我们总结了一个项目的结果，该项目试图基于从著名植物黑升麻提取物中鉴定出的新型天然产物开发此类γ-分泌酶调节剂。在分离出化合物（SPI-014）后，开展了广泛的药物化学研究，以确定该化合物及相关半合成化合物的构效关系。克服了该化合物的主要代谢和物理化学缺陷，包括用更稳定的替代基团取代糖基和乙酰基部分，从而改善了药物性质，并得到了开发候选物（SPI-1865）。然而，意外的脱靶肾上腺毒性使这一系列化合物无法进入临床开发阶段。
