Novel orally active morpholine N-arylsulfonamides γ-secretase inhibitors with low CYP 3A4 liability

A new class of 2,6-disubstituted morpholine N-arylsulfonamide γ-secretase inhibitors was designed based on the introduction of a morpholine core in lieu or piperidine in our lead series. This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Aβ levels in Tg CRND8 mice upon oral administration were identified.

Graphical abstractThe design of a new class of N-arylsulfonamide γ-secretase inhibitors based on the introduction of a morpholine core is reported. Compounds devoid of CYP 3A liability and active orally in a Tg CRND8 mice model of Alzheimer’s disease were obtained.Figure optionsDownload full-size imageDownload as PowerPoint slide