Discovery of a Tetrahydrobenzisoxazole Series of γ‑Secretase Modulators

The design and synthesis of a new series of tetrahydrobenzisoxazoles as modulators of γ-secretase activity and their structure–activity relationship (SAR) will be detailed. Several compounds are active γ-secretase modulators (GSMs) with good to excellent selectivity for the reduction of Aβ₄₂ in the cellular assay. Compound <b>14a</b> was tested <i>in vivo</i> in a nontransgenic rat model and was found to significantly reduce Aβ₄₂ in the CNS compartment compared to vehicle-treated animals (up to 58% reduction of cerebrospinal fluid Aβ₄₂ as measured 3 h after an acute oral dosing at 30 mg/kg)

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 <b>18a­(−)</b> 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