IDENTIFICATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR LIGANDS FROM A BIASED CHEMICAL LIBRARY

Background: The peroxisome proliferator-activated receptors (PPARs) we re cloned as orphan members of the nuclear receptor superfamily of tra nscription factors. The identification of subtype-selective ligands fo r PPAR alpha and PPAR gamma has led to the discovery of their roles in the regulation of lipid metabolism and glucose homeostasis. No subtyp e-selective PPAR delta ligands are available and the function of this subtype is currently unknown. Results: A three-component library was d esigned in which one of the monomers was biased towards the PPARs and the other two monomers were chosen to add chemical diversity. Synthesi s and screening of the library resulted in the identification of pools with activity on each of the PPAR subtypes. Deconvolution of the pool s with the highest activity on PPAR delta led to the identification of GW 2433 as the first high-affinity PPAR delta ligand. [H-3]GW 2433 is an effective radioligand for use in PPAR delta competition-binding as says. Conclusions: The synthesis of biased chemical libraries is an ef ficient approach to the identification of lead molecules for members o f sequence-related receptor families. This approach is well suited to the discovery of small-molecule ligands for orphan receptors.