A number of dipeptide aldehydes possessing DAPT partial structures and certain amino- terminal building blocks were synthesized through Weinreb amide and evaluated on the prevention of proteolytic processing of amyloid precursor protein (APP)-695-GVP or its C-terminal fragment (C99-GVP) as γ-secretase inhibitors via observation of luciferase expression. Comparison of all the synthetic aldehydes possessing Ile-Leu residue, compounds with N-terminal 3,5-difluoro-phenylacetyl (19) or 3,5-dimethoxyphenylacetyl moiety (17a) improved the excellent levels of γ-secretase inhibition. Intriguingly, the hydrophobic Ile-Leu residue was shown the best fit to the P2-P1 binding pocket of the target enzyme. Our results suggested that the selected dipeptide aldehydes may act as allosteric inhibitors by targeting the γ-secretase complex at a novel site discrete from the binding site for non-transition state analogues, such as DAPT and Compound E.