Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library

Background: The peroxisome proliferator-activated receptors (PPARs) were cloned as orphan members of the nuclear receptor superfamily of transcription factors. The identification of subtype-selective ligands for PPARα and PPARγ has led to the discovery of their roles in the regulation of lipid metabolism and glucose homeostasis. No subtype-selective PPARδ ligands are available and the function of this subtype is currently unknown. Results: A three-component library was designed in which one of the monomers was biased towards the PPARs and the other two monomers were chosen to add chemical diversity. Synthesis and screening of the library resulted in the identification of pools with activity on each of the PPAR subtypes. Deconvolution of the pools with the highest activity on PPARδ led to the identification of GW 2433 as the first high-affinity PPARδ ligand. [³H]GW 2433 is an effective radioligand for use in PPARδ competition-binding assays. Conclusions: The synthesis of biased chemical libraries is an efficient approach to the identification of lead molecules for members of sequence-related receptor families. This approach is well suited to the discovery of small-molecule ligands for orphan receptors.