Natural Product and Natural Product-Derived Gamma Secretase Modulators from Actaea Racemosa ExtractsReport as inadecuate




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1

Aria Neurosciences, Incorporated, 295 Washington Ave, Suite 4N, Hamden, CT 06518, USA

2

Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, 533 Tower Road, Ithaca, NY 14853-1801, USA

3

Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA

4

Biogen, 115 Broadway Street, Cambridge, MA 02142, USA

5

Department of Veterans Affairs, ENR Memorial Veterans Hospital, 200 Springs Road, Bedford, MA 01730, USA





*

Author to whom correspondence should be addressed.



Academic Editor: Shufeng Zhou

Abstract 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. View Full-Text

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





Author: Mark A. Findeis 1,* , Frank C. Schroeder 2, Steffen P. Creaser 3, Timothy D. McKee 4 and Weiming Xia 5

Source: http://mdpi.com/



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