Triazoles as γ-secretase modulators.
Christian Fischer1, Susan L Zultanski, Hua Zhou
1Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. christian_fischer@merck.com
Bioorganic & Medicinal Chemistry Letters
|May 28, 2011
Summary
Novel aryl triazoles effectively modulate gamma secretase activity. These compounds show excellent pharmacokinetics and reduce central amyloid-beta 42 levels in rats, offering potential for Alzheimer's disease therapeutics.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Drug Discovery
Background:
- Gamma secretase modulators (GSMs) are investigated for Alzheimer's disease treatment.
- Non-acidic GSMs often utilize olefin moieties.
- Exploring alternative heterocyclic scaffolds is crucial for novel drug development.
Purpose of the Study:
- To synthesize and evaluate novel aryl triazoles as gamma secretase modulators (GSMs).
- To identify five-membered heterocycles as potential replacements for olefins in non-acidic GSMs.
- To assess the in vivo efficacy of identified compounds in reducing amyloid-beta 42.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted on aryl triazole derivatives.
- Synthesis of a range of five-membered heterocycles was performed.
- In vivo evaluation involved assessing central amyloid-beta 42 lowering in Sprague-Dawley rats.
Main Results:
- 1,2,3-C-aryl-triazoles were identified as effective replacements for olefins.
- The synthesized aryl triazoles demonstrated good modulation of gamma secretase activity.
- Compounds exhibited excellent pharmacokinetic profiles and significant central lowering of amyloid-beta 42 in vivo.
Conclusions:
- Aryl triazoles represent a promising class of novel gamma secretase modulators.
- These compounds offer a viable alternative to olefin-based GSMs.
- The findings support the potential of aryl triazoles for Alzheimer's disease therapeutic strategies.
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