The cleavage of amyloid precursor protein via �- and then ?-secretases leads to the production of amyloid-� peptides (A�) of various chain lengths. This production of A� is thought to be a leading factor in the development of Alzheimer's disease. Of the various A� fragments generated, A�-42 is prone to forming amyloid plaques in the brain. The development of ?-secretase modulators (GSM's) provides a means to alter the production from A�-42 to shorter, more soluble A� fragments. In addition, GSM's provide an attractive alternative to ?-secretase inhibitors since they do not block other ?-secretase functions such as Notch processing. We report on a series of oxadiazoline and oxadiazine GSM's with novel heterocycle replacements of the terminal methyl-imidazole moiety of our earlier leads. In addition to possessing a modulator profile, these molecules reduced A�-42 in rat CSF, and in some cases the reduction was equal to the methyl-imidazole control.

C-linked replacements of the methyl-imidazole subunit of γ-secretase modulators

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.