Structural development studies of PPARs ligands based on tyrosine scaffold

• Chemical modification of PPARα/γ dual agonist GW409544 gives selective PPARγ agonists.
• Stilbene and phenyldiazene groups confirm to be bioisosteres.
• Phenyldiazenes unsubstituted on the distal phenyl ring undergo isomerization.

PPARs are nuclear receptors with a critical physiological role in lipid and glucose metabolism. As part of our effort to develop new and selective PPAR agonists containing stilbene and its bioisoster phenyldiazene, novel analogs were synthesized starting from tyrosine and evaluated as PPAR agonists. We tested the effects of phenyloxazole replacement of GW409544, a well-known PPARα/γ dual agonist, with stilbene or phenyldiazene moiety, spaced by an ether bridge to tyrosine portion. These structural modifications provided potent and selective PPARγ agonists. Molecular docking studies performed on these new compounds complemented the experimental results and allowed to gain some insights into the nature of binding of the ligands.

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