Small conformationally restricted piperidine N-arylsulfonamides as orally active γ-secretase inhibitors

Abstract The design and development of a new class of small 2,6-disubstituted piperidine N -arylsulfonamide γ-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Aβ levels in Tg CRND8 mice were identified as potential treatments for Alzheimer’s disease.