Part 1: Notch-sparing -secretase inhibitors: The identification of novel naphthyl and benzofuranyl amide analogs.
Additional Document Info
-Secretase is one of two proteases directly involved in the production of the amyloid -peptide (A), which is pathogenic in Alzheimer's disease. Inhibition of -secretase to suppress the production of A should not block processing of one of its alternative substrates, Notch1 receptors, as interference with Notch1 signaling leads to severe toxic effects. In the course of our studies to identify -secretase inhibitors with selectivity for APP over Notch, 1 [3-(benzyl(isopropyl)amino)-1-(naphthalen-2-yl)propan-1-one] was found to inhibit -secretase-mediated A production without interfering with -secretase-mediated Notch processing in purified enzyme assays. As 1 is chemically unstable, efforts to increase the stability of this compound led to the identification of 2 [naphthalene-2-carboxylic acid benzyl-isopropyl-amide] which showed similar biological activity to compound 1. Synthesis and evaluation of a series of amide analogs resulted in benzofuranyl amide analogs that showed promising Notch-sparing -secretase inhibitory effects. This class of compounds may serve as a novel lead series for further study in the development of -secretase inhibitors.