Natural Product and Natural Product-Derived Gamma Secretase Modulators from Actaea Racemosa Extracts

Medicines

Mark A. Findeis²  Frank C. Schroeder⁵  Steffen P. Creaser³  Timothy D. McKee¹  Weiming Xia⁴ 

[1] Biogen, 115 Broadway Street, Cambridge, MA 02142, USA; E-Mail:;Aria Neurosciences, Incorporated, 295 Washington Ave, Suite 4N, Hamden, CT 06518, USA;Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA; E-Mail:;Department of Veterans Affairs, ENR Memorial Veterans Hospital, 200 Springs Road, Bedford, MA 01730, USA; E-Mail:;Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, 533 Tower Road, Ithaca, NY 14853-1801, USA; E-Mail:

关键词: Alzheimer’s disease;    amyloid precursor protein;    beta-amyloid;    gamma secretase modulator;    Actaea racemosa;    black cohosh;    natural product;    SPI-014;    SPI-1865;   

DOI  :  10.3390/medicines2030127

来源: mdpi

【 摘 要 】

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 Actaea racemosa, the well-known botanical black cohosh. Following isolation of compound 1 (SPI-014), an extensive medicinal chemistry effort was undertaken to define the SAR of 1 and related semisynthetic compounds. Major metabolic and physicochemical liabilities in 1 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 25 (SPI-1865). Unanticipated off-target adrenal toxicity, however, precluded advancement of this series of compounds into clinical development.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.