Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175

• Oximes in the MOIMM configuration behave as bioisosteric groups of benzene ring.
• Dual PPARα/γ activity seems to produce synergism on both receptor subtypes.
• Stereochemistry confirms to play a crucial role in the PPAR activation.

The effects resulting from the introduction of an oxime group in place of the distal aromatic ring of the diphenyl moiety of LT175, previously reported as a PPARα/γ dual agonist, have been investigated. This modification allowed the identification of new bioisosteric ligands with fairly good activity on PPARα and fine-tuned moderate activity on PPARγ. For the most interesting compound (S)-3, docking studies in PPARα and PPARγ provided a molecular explanation for its different behavior as full and partial agonist of the two receptor isotypes, respectively. A further investigation of this compound was carried out performing gene expression studies on HepaRG cells. The results obtained allowed to hypothesize a possible mechanism through which this ligand could be useful in the treatment of metabolic disorders. The higher induction of the expression of some genes, compared to selective agonists, seems to confirm the importance of a dual PPARα/γ activity which probably involves a synergistic effect on both receptor subtypes.

A new class of oximes bioisosteric of the previously reported PPARα/γ dual agonist LT175 is here reported. For the most interesting compound (S)-3, docking experiments and gene expression studies were performed allowing to hypothesize the molecular and biochemical mechanisms of action.Figure optionsDownload as PowerPoint slide