Substituted 4-morpholine N-arylsulfonamides as γ-secretase inhibitors
Zhiqiang Zhao1, Dmitri A Pissarnitski1, Hubert B Josien1
1Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
European Journal of Medicinal Chemistry
|August 26, 2016
Summary
Researchers developed novel 4-morpholine sulfonamide γ-secretase inhibitors (GSIs) that reduce CYP liabilities and amyloid-beta (Aβ) in an Alzheimer
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Pharmacology
Background:
- γ-secretase inhibitors (GSIs) are investigated for Alzheimer's disease (AD) treatment.
- Previous GSI series exhibited CYP liabilities and suboptimal activity.
- Optimizing GSI profiles is crucial for therapeutic development.
Purpose of the Study:
- To design, synthesize, and characterize a novel series of substituted 4-morpholine sulfonamide GSIs.
- To improve the pharmacological profile, including reduced CYP liabilities and enhanced γ-secretase inhibition.
- To evaluate the in vivo efficacy of selected compounds in an Alzheimer's disease animal model.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted.
- Synthesis of a novel series of 4-morpholine sulfonamides.
- In vitro assays for γ-secretase inhibition and CYP liability assessment.
- In vivo studies in transgenic AD animal models to measure amyloid-beta (Aβ) reduction.
Main Results:
- The novel 4-morpholine sulfonamide series demonstrated improved γ-secretase inhibition.
- Several compounds showed reduced cytochrome P450 (CYP) liabilities compared to previous series.
- Selected inhibitors significantly reduced amyloid-beta (Aβ) levels after oral administration in an AD model.
Conclusions:
- Substituted 4-morpholine sulfonamides represent a promising class of GSIs.
- This series offers potential for improved therapeutic index in Alzheimer's disease treatment.
- Further development of these compounds may lead to effective AD therapies.
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