Fibrate-derived N-(methylsulfonyl)amides with antagonistic properties on PPARα

The identification of novel PPAR ligands represents an attractive research to fully understand the complex biological pathways regulated by these receptors. Selective PPAR modulators, inverse agonists and antagonists of three PPAR isoforms could help to clarify biological effects on lipid and glucose homeostasis. Here we describe the identification of a group of N-(methylsulfonyl)amides, derived from PPARα agonist carboxylic acids. Transactivation and FRET assay confirmed an antagonist behaviour on PPARα for some of these compounds, with submicromolar IC50. A preliminary analysis on selectivity α/γ revealed different profiles of inhibition or activation.

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► Synthesis of N-(methylsulfonyl)amides containing the benzothiazole scaffold.
► Transactivation assay for agonistic and antagonistic effect on PPARα activation.
► Preliminary structure–activity relationships discussion.
► Binding to PPARα by means of a TR-FRET assay.