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 gamma-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent ?-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-? (A beta) 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 ?-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.