Recent progress in the medicinal chemistry of gamma-secretase inhibitors
Richard E Olson1, Charles F Albright
1Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Richard.Olson@BMS.com
Abstract:
Abeta is implicated in the initiation and progression of Alzheimer's disease (AD) by the phenotypic analysis of mutations in three human genes that lead to inherited, early forms of AD and data from preclinical studies. Based on this evidence, gamma-secretase inhibitors are being actively pursued as potential AD therapeutics to reduce Abeta formation. This manuscript reviews recent progress in the medicinal chemistry of three major classes of gamma-secretase inhibitors: peptide isosteres, azepines, and sulfonamides. Peptide isosteres have been useful for demonstrating that presenilin is the catalytic subunit of gamma-secretase and probing the active site. The peptidic nature of these inhibitors has, however, interfered with their utility for in vivo studies. Instead, the pharmaceutical industry has focused on optimizing azepines and sulfonamides. Both azepines and sulfonamides bind to a common, allosteric site on presenilin that differs from the active site identified by the peptide isosteres. Significant progress in the optimization of both azepines and sulfonamides has led to compounds that inhibit brain Abeta synthesis in preclinical models and has culminated in the identification of gamma-secretase inhibitors, including LY-450139 and MK-0752, for human trials.
Insights
Gamma-secretase inhibitors targeting amyloid-beta (Abeta) formation are promising Alzheimer's disease (AD) therapeutics. Medicinal chemistry efforts focus on azepines and sulfonamides, showing potential for inhibiting Abeta synthesis in preclinical models.
Area of Science:
- Neuroscience
- Medicinal Chemistry
- Pharmacology
Background:
- Amyloid-beta (Abeta) peptides are central to Alzheimer's disease (AD) pathogenesis.
- Mutations in human genes linked to early-onset AD implicate Abeta in disease initiation and progression.
- Gamma-secretase inhibitors are investigated as therapeutics to reduce Abeta production.
Purpose of the Study:
- To review recent advancements in the medicinal chemistry of gamma-secretase inhibitors.
- To discuss the development of peptide isosteres, azepines, and sulfonamides as potential AD therapeutics.
- To highlight compounds progressing towards clinical trials for Alzheimer's disease.
Main Methods:
- Review of scientific literature on gamma-secretase inhibitor development.
- Analysis of structure-activity relationships for different inhibitor classes.
- Evaluation of preclinical data on Abeta synthesis inhibition.
Main Results:
- Peptide isosteres were valuable for understanding gamma-secretase but limited for in vivo use.
- Azepines and sulfonamides bind to an allosteric site on presenilin, distinct from the active site.
- Optimized azepines and sulfonamides inhibit brain Abeta synthesis in preclinical models.
Conclusions:
- Azepines and sulfonamides represent promising therapeutic strategies for Alzheimer's disease.
- Compounds like LY-450139 and MK-0752 have advanced to human clinical trials.
- Targeting gamma-secretase offers a viable approach to reduce Abeta formation in AD.
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