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P3 cap modified Phe*-Ala series BACE inhibitors
Shu-Hui Chen1, Jason Lamar, Deqi Guo
1Lilly Research Laboratories, Discovery Chemistry Division and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. chen_shu-hui@lilly.com
Bioorganic & Medicinal Chemistry Letters
|December 20, 2003
Summary
Researchers modified BACE inhibitors to improve blood-brain barrier penetration. New P3 cap modifications yielded potent inhibitors with nanomolar enzyme activity and micromolar whole cell activity, enhancing drug development potential.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Drug Discovery
Background:
- Beta-secretase 1 (BACE-1) is a key target for Alzheimer's disease treatment.
- Optimizing physicochemical properties like molecular weight and log D is crucial for BACE inhibitor efficacy, particularly for blood-brain barrier (BBB) penetration.
- The P3 position of BACE inhibitors is a potential site for modification to enhance drug-like properties.
Purpose of the Study:
- To synthesize and evaluate novel BACE inhibitors with modified P3 cap groups.
- To reduce molecular weight and adjust log D values for improved BBB penetration and bioavailability.
- To identify structure-activity relationships (SAR) of P3 cap modifications on BACE inhibitory activity.
Main Methods:
- Synthesis of BACE inhibitor analogues by replacing the P3NHBoc moiety with various polar functional groups (amino, hydroxyl, fluorine).
- In vitro enzyme inhibition assays to determine BACE-1 IC(50) values.
- Whole cell assays to assess the cellular activity of the synthesized compounds.
Main Results:
- Several series of P3 cap modified BACE inhibitors were successfully synthesized.
- Promising inhibitors (e.g., compounds 15 and 19) exhibited potent BACE-1 inhibition with IC(50) values below 50 nM.
- These compounds also demonstrated significant whole cell activity with IC(50) values around 1 microM.
Conclusions:
- Modification of the P3 cap moiety is an effective strategy for developing potent BACE inhibitors.
- Optimized P3 cap structures can lead to compounds with favorable properties for BBB penetration and therapeutic application.
- The identified inhibitors represent promising leads for further development as Alzheimer's disease therapeutics.