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ID: ALA3627709
Journal: J Med Chem
Title: Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors.
Authors: Zhao Z, Pissarnitski DA, Josien HB, Wu WL, Xu R, Li H, Clader JW, Burnett DA, Terracina G, Hyde L, Lee J, Song L, Zhang L, Parker EM.
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.
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