Stereochemical analysis of (hydroxyethyl)urea peptidomimetic inhibitors of gamma-secretase

(Hydroxyethyl)urea peptidomimetics systematically altered at positions P2-P3' with hydrophobic D-amino acids were synthesized. An all D-amino acid containing analogue was identified that effectively blocked gamma-secretase activity in a cell-free system (IC50 = 30 nM). Systematic alteration of the stereocenters of a potent compound revealed interdependence between the various positions. Although typically less potent than their L-peptidomimetic counterparts, selected all D-amino acid containing analogues were equipotent to their counterparts in a cell-based assay when incubated for extended times.