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

Abstract

The ligand-regulated nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) 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 NCI/NIH Developmental Therapeutics Program for inhibitory PPARβ/δ 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-bromophenyl)-3-{[4-(1-methyl-piperazine)amino]phenyl}acrylonitrile (DG172), a novel PPARβ/δ-selective ligand showing high binding affinity (IC(50) = 27 nM) and potent inverse agonistic properties. 37 selectively inhibited the agonist-induced activity of PPARβ/δ, enhanced transcriptional corepressor recruitment, and down-regulated transcription of the PPARβ/δ target gene Angptl4 in mouse myoblasts (IC(50) = 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 PPARβ/δ.

The Inverse Agonist DG172 Triggers a PPARβ/δ-Independent Myeloid Lineage Shift and Promotes GM-CSF/IL-4-Induced Dendritic Cell Differentiation

“…All values represented by bars were calculated relative to the effect of DG172 [DG172 value/dimethylsulfoxide (DMSO) value normalized to 100%] at a concentration of 1 mM for all compounds. IC 50 values were determined by titration over a range of 0.1 nM-10 mM (competitive TR-FRET) as previously described (Lieber et al, 2012) (n.d., not determined). Data represent the average of triplicates.…”

“…DG172, its derivatives, and ST247 were synthesized as previously described (Lieber et al, 2012;Toth et al, 2012). GW501516 was purchased from Axxora (Lörrach, Germany).…”

“…Synthetic antagonistic ligands for PPARb/d have been explored to a much lesser extent, but several inhibitory compounds have been described over the past years. These include the irreversible inhibitor and partial PPARg agonist GSK3787 (Palkar et al, 2010;Shearer et al, 2010), the PPARb/dspecific GSK0660 (Shearer et al, 2008) and its improved derivative methyl 3-{N-[4-(hexylamino)-2-methoxyphenyl]sulfamoyl} thiophene-2-carboxylate (ST247) (Naruhn et al, 2011;Toth et al, 2012), and the stilbene (Z)-2-(2-bromophenyl)-3-{[4-(1-methylpiperazine)amino]phenyl}acrylonitrile (DG172) (Lieber et al, 2012). These ligands act as inverse agonists, as indicated by their inhibitory effect on the basal expression of PPARb/d target genes and an increased recruitment of transcriptional corepressors (Naruhn et al, 2011).…”

“…These ligands act as inverse agonists, as indicated by their inhibitory effect on the basal expression of PPARb/d target genes and an increased recruitment of transcriptional corepressors (Naruhn et al, 2011). DG172 is a PPARb/d-selective compound characterized by high affinity and potent repressive effects on PPARb/d target genes (Lieber et al, 2012).…”

Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618

“…the analogue ST247 (5), with improved bioavailability and binding affinity [19,20]. The same research group recently developed the acrylonitrile compound DG172 (6) which exhibited potent PPARβ/δ antagonism and oral bioavailability [21]. As carboxylic acids are canonical agonists of the PPAR receptors, it is notable that also SR13904 (7) [22], reported by Zaveri et al as well as the acid 3a (8) [23], reported by Kasuga et al, exhibited PPARβ/δ antagonism.…”