4-Substituted cyclohexyl sulfones as potent, orally active γ-secretase inhibitors

…, P Morentin-Gutierrez, R Mortishire-Smith…

Index: Churcher, Ian; Beher, Dirk; Best, Jonathan D.; Castro, Jose L.; Clarke, Earl E.; Gentry, Amy; Harrison, Timothy; Hitzel, Laure; Kay, Euan; Kerrad, Sonia; Lewis, Huw D.; Morentin-Gutierrez, Pablo; Mortishire-Smith, Russell; Oakley, Paul J.; Reilly, Michael; Shaw, Duncan E.; Shearman, Mark S.; Teall, Martin R.; Williams, Susie; Wrigley, Jonathan D.J. Bioorganic and Medicinal Chemistry Letters, 2006 , vol. 16, # 2 p. 280 - 284

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Citation Number: 56

Abstract

The protease γ-secretase plays a pivotal role in the synthesis of pathogenic amyloid-β in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based γ-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Aβ (40) lowering in vivo (eg, compound 32, MED 1mg/kg po in APP-YAC mice).