Fluorinated piperidine acetic acids as γ-secretase modulators

The discovery and optimization of a novel class of difluoropiperidine acetic acid γ-secretase modulators is described. These compounds selectivity inhibit the formation of the more pathogenic Aβ42 without impacting Aβ40 production and, importantly, undesired Notch cleavage. We report herein a novel series of difluoropiperidine acetic acids as modulators of γ-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective β-difluorination with Selectfluor®. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Aβ42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250 mg/kg per day, AUC 0–24 = 2100 μM h) did not exhibit Notch-related effects.