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

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.

Graphical abstractThe design and development of small 2,6-disubstituted piperidine N-arylsulfonamide γ-secretase inhibitors is reported. Compounds active orally and with less CYP liability than earlier leads were obtained.Figure optionsDownload full-size imageDownload as PowerPoint slide