June 17, 2013
More weapons are added to the β-secretase inhibitor arsenal. Inventors A. Minidis, F. Rahm, and J. Viklund disclose monofluoro compounds represented by formula 1 that inhibit the enzyme β-secretase, also known as β-site amyloid–cleaving enzyme (BACE or BACE-1). It is possible that these compounds can be used to treat and/or prevent amyloid β (Aβ)–related pathologies and β-amyloid angiopathy such as Down syndrome and Alzheimer’s disease.
BACE is a membrane-bound type 1 protein that is abundantly expressed in brain tissue. Its activity is implicated generating Aβ peptide from amyloid precursor protein; it is believed to be the rate-limiting step in the production of Aβ. Inhibiting BACE activity with molecules such as the inventors describe could reduce the production of Aβ and slow the formation of amyloid plaques and the progression of Alzheimer’s disease and other disorders that involve the deposition of Aβ or its fragments.
The figure shows four representative structures of the compounds of formula 1. Two of the assays used to evaluate these compounds were the TR-FRET assay and the sAPPβ release assay. The inventors state that typical IC50 values for the tested compounds are in the range of 10–2–105 nM. The values for the four examples are shown in the table.