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Design of potent PPARalpha agonists.
Per Sauerberg1, John P Mogensen, Lone Jeppesen
1Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark.
Bioorganic & Medicinal Chemistry Letters
|March 24, 2007
Summary
Researchers designed potent PPARalpha agonists by analyzing the ligand binding pocket. Optimum potency and selectivity were achieved using specific substituent volumes, leading to highly selective compounds.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
Background:
- Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating metabolism and inflammation.
- PPAR subtypes (PPARα, PPARγ, PPARδ) have distinct roles, making subtype-selective agonists desirable drug candidates.
Purpose of the Study:
- To computationally design potent and selective PPARalpha agonists.
- To identify structural features correlating with PPARalpha activity and selectivity.
Main Methods:
- Computational analysis of the ligand binding pockets of PPARα, PPARγ, and PPARδ.
- Structure-based drug design principles were applied.
Main Results:
- Optimal PPARα potency and selectivity were associated with substituents possessing a van der Waals volume of approximately 260.
- Compound 6 demonstrated high PPARα potency (0.002 μM) and significant selectivity over PPARγ (410-fold) and PPARδ (2000-fold).
Conclusions:
- Computational analysis is effective for designing selective PPAR agonists.
- Substituent van der Waals volume is a critical factor for achieving PPARα potency and selectivity.
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