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- W1889416002 abstract "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." @default.
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- W1889416002 date "2015-11-06" @default.
- W1889416002 modified "2023-10-08" @default.
- W1889416002 title "Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors" @default.
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- W1889416002 doi "https://doi.org/10.1021/acs.jmedchem.5b00774" @default.
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