Discovery of a Novel, Potent Spirocyclic Series of γ‑Secretase Inhibitors

In the present paper, we described
the design, synthesis, SAR,
and biological profile of a novel spirocyclic sulfone series of γ-secretase
inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic
ring system to stabilize the active chair conformation of the parent
γ-secretase inhibitors. The resulting series is devoid of the
CYP2C9 inhibition liability of MRK-560. A few representative analogs
were assessed in a nontransgenic animal model of Alzheimer’s
disease (AD), demonstrating reduction of amyloid-β (Aβ)
in the CNS after acute oral dosing. A spirocyclic phosphonate was
identified as the optimal ring system for both potency and pharmacokinetics.
Compared to GSIs studied in the clinic, representative spirocyclic
phosphonate 18a­(−) features improved selectivity
for the inhibition of the PS-1 isoform of γ-secretase (33-fold
vs PS-2), which may alleviate the adverse effect profile of the clinical
GSIs.