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Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists
Bernd Kuhn1, Hans Hilpert, Jörg Benz
1F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. bernd.kuhn@roche.com
Bioorganic & Medicinal Chemistry Letters
|June 2, 2006
Summary
Researchers developed novel dual agonists targeting PPARalpha/gamma for type 2 diabetes and dyslipidemia. Structure-based design yielded potent indole-based compounds selective against PPARdelta, offering new therapeutic avenues.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Structural Biology
Background:
- Type 2 diabetes and dyslipidemia are significant global health concerns.
- Peroxisome proliferator-activated receptors (PPARs) are key targets for metabolic disease treatment.
- PPARalpha/gamma dual agonists offer potential for synergistic therapeutic effects.
Purpose of the Study:
- To identify novel PPARalpha/gamma co-agonists using structure-based design.
- To develop potent and selective activators for type 2 diabetes and dyslipidemia treatment.
- To explore the structure-activity relationships (SAR) of identified compounds.
Main Methods:
- Structure-based drug design utilizing a 1,5-disubstituted indole scaffold.
- Synthesis and in vitro evaluation of propionic acid derivatives.
- X-ray crystallography to determine the binding mode of PPARgamma agonists.
Main Results:
- Identification of potent submicromolar dual PPARalpha/gamma agonists (Compounds 13, 24, 28).
- Demonstration of selectivity against the PPARdelta isoform.
- Elucidation of SAR through X-ray complex structure analysis of PPARgamma with compound 13.
Conclusions:
- The 1,5-disubstituted indole scaffold is effective for developing PPARalpha/gamma dual agonists.
- The identified compounds represent promising drug candidates for type 2 diabetes and dyslipidemia.
- Structural insights rationalize the observed activity and selectivity, guiding future drug optimization.
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