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Cyclic sulfamide gamma-secretase inhibitors
Tim Sparey1, Dirk Beher, Jonathan Best
1Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. tim_sparey@merck.com
Bioorganic & Medicinal Chemistry Letters
|August 2, 2005
Summary
Researchers developed novel cyclic sulfamides targeting gamma-secretase. A key compound showed potent activity, reducing amyloid-beta in mouse models, offering potential Alzheimer's disease therapeutic strategies.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Pharmacology
Background:
- Alzheimer's disease pathogenesis involves amyloid-beta (Abeta) peptide accumulation.
- Gamma-secretase is a key enzyme in amyloid precursor protein processing and Abeta production.
Purpose of the Study:
- To develop novel N-alkyl-substituted cyclic sulfamides as gamma-secretase inhibitors.
- To identify compounds with potent in vitro and in vivo activity against gamma-secretase.
Main Methods:
- Synthesis and chemical modification of N-alkyl-substituted cyclic sulfamides.
- In vitro enzymatic assays to determine gamma-secretase activity.
- In vivo studies in APP-YAC mouse models to assess brain Abeta40 levels after oral administration.
Main Results:
- Development of a novel series of cyclic sulfamides.
- Identification of N-trifluoroethyl-substituted compounds with significant in vitro and in vivo gamma-secretase activity.
- One compound demonstrated subnanomolar activity and reduced brain Abeta40 levels in APP-YAC mice following oral dosing.
Conclusions:
- N-trifluoroethyl-substituted cyclic sulfamides represent a promising class of gamma-secretase inhibitors.
- The lead compound warrants further investigation as a potential therapeutic agent for Alzheimer's disease.