4-substituted cyclohexyl sulfones as potent, orally active gamma-secretase inhibitors |
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| Authors: | Churcher Ian Beher Dirk Best Jonathan D Castro José 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 |
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| Affiliation: | Department of Medicinal Chemistry, The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. ian_churcher@merck.com |
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| Abstract: | ![]()
The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice). |
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