GW-0742 vs SLU-PP-915

Metabolic

Metabolic

Research Only

Research Only

GW-0742 is a high-affinity, highly selective agonist of human PPARδ (EC50 = 1.1 nM for hPPARδ transactivation vs ~1.1 µM for hPPARα and ~2 µM for hPPARγ), conferring ~1000-fold selectivity for PPARδ over the other PPAR subtypes. Upon activation, PPARδ heterodimerizes with RXR and binds PPAR-response elements (PPREs) to alter transcription of genes governing fatty-acid oxidation, glucose utilization, and inflammatory signaling. In mice, however, GW-0742-induced hepatomegaly, hepatic/skeletal-muscle peroxisome proliferation, and skeletal myopathy were shown to be predominantly mediated by off-target PPARα cross-activation rather than PPARδ—a mechanism-based toxicity concern at animal-study exposures.

The estrogen-related receptors (ERRα/β/γ) are orphan nuclear receptors that act as master transcriptional regulators of oxidative metabolism, driving mitochondrial biogenesis, oxidative phosphorylation, fatty-acid oxidation, and the TCA cycle — largely as partners of the PGC-1 coactivators. SLU-PP-915 binds and activates all three ERR isoforms with an EC50 of roughly 400 nM at each. In its medicinal-chemistry design, the phenol and aniline groups of earlier ERR agonists were replaced with a boronic-acid moiety on a disubstituted thiophene scaffold, which preserved receptor activity while improving microsomal metabolic stability and oral exposure. In cells and in rodents it upregulates canonical ERR target genes including PGC-1α, lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase 4 (PDK4), and DNA-damage-inducible transcript 4 (DDIT4).