(Z)-2-(2-Bromophenyl)-3-{[4-(1-methyl-piperazine)amino]phenyl}acrylonitrile (DG172): An Orally Bioavailable PPARβ/δ-Selective Ligand with Inverse Agonistic Properties

The ligand-regulated nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) is a potential pharmacological target due to its role in disease-related biological processes. We used TR-FRET-based competitive ligand binding and coregulator interaction assays to screen 2693 compounds of the Open Chemical Repository of the NCl/NIH Developmental Therapeutics Program for inhibitory PPAR beta/delta ligands. One compound, (Z)-3-(4-dimethylamino-phenyl)-2-phenyl-acrylonitrile, was used for a systematic SAR study. This led to the design of derivative 37, (Z)-2-(2-bromopheny1)-3-{[4-(1-methyl-piperazine)amino]phenyl}acrylonitrile (DG172), a novel PPAR beta/delta-selective ligand showing high binding affinity (IC50 = 27 nM) and potent inverse agonistic properties. 37 selectively inhibited the agonist-induced activity of PPAR beta/delta, enhanced transcriptional corepressor recruitment, and down-regulated transcription of the PPAR beta/delta target gene Angptl4 in mouse myoblasts (IC50 = 9.5 nM). Importantly, 37 was bioavailable after oral application to mice with peak plasma levels in the concentration range of its maximal inhibitory potency, suggesting that 37 will be an invaluable tool to elucidate the functions and therapeutic potential of PPAR beta/delta.