GW-0742 vs SR-9011

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.

SR-9011 is an agonist of the nuclear receptors REV-ERBα and REV-ERBβ. Binding enhances REV-ERB-mediated transcriptional repression (via NCoR corepressor recruitment), repressing core clock genes such as Bmal1 and downstream metabolic genes in liver, skeletal muscle, and adipose tissue (Solt et al., Nature 2012). All mechanistic data are from cells and rodents.