Discovery of amide and heteroaryl isosteres as carbamate replacements in a series of orally active γ-secretase inhibitors

Abstract The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine N -arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of γ-secretase inhibitors. Selected compounds showed significant reduction of Aβ levels upon oral dosing in a transgenic murine model of Alzheimer’s disease.