selectfluor and Disease-Models--Animal

We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.

Topics: Acetates; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Diazonium Compounds; Disease Models, Animal; Fluorine; Mice; Mice, Transgenic; Peptide Fragments; Piperidines; Rats; Receptors, Notch