Discovery of aryl aminothiazole γ-secretase modulators with novel effects on amyloid β-peptide production

Abstract

A series of analogs based on a prototype aryl aminothiazole {gamma}-secretase modulator (GSM) were synthesized and tested for their effects on the profile of 37-to-42-residue amyloid {beta}-peptides (A{beta}), generated through processive proteolysis of precursor protein substrate by {gamma}-secretase. Certain substitutions on the terminal aryl D ring resulted in an altered profile of A{beta} production compared to that seen with the parent molecule. Small structural changes led to concentration-dependent increases in A{beta}37 and A{beta}38 production without parallel decreases in their precursors A{beta}40 and A{beta}42, respectively. The new compounds therefore apparently also stimulate carboxypeptidase trimming of A{beta} peptides [≥]43 residues, providing novel chemical tools for mechanistic studies of processive proteolysis by {gamma}-secretase. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY