Design and synthesis of piperazine derivatives as a novel class of γ-secretase modulators that selectively lower Aβ42 production

Novel piperazine derivatives as γ-secretase modulators (GSMs) were prepared and tested for their ability to selectively lower Aβ42 production. Lead compound 3, with selective Aβ42-lowering activity, was modified by replacing its imidazolylphenyl moiety with an oxazolylphenyl moiety. Optimization of the urea group significantly improved mouse microsomal stability, while retaining both activity and selectivity. These efforts led to the successful identification of an orally available and brain-penetrant GSM, 6j, which selectively reduced brain Aβ42 in mice.

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