GW-0742 vs SLU-PP-332

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.

SLU-PP-332 activates all three ERR isoforms (α, β, γ) with a modest potency preference for ERRα — orphan nuclear receptors that regulate oxidative metabolism gene programs. Activation drives PGC-1α co-activator pathways, mitochondrial biogenesis (TFAM, NRF1), fatty acid oxidation (CPT1B, ACADM), and a shift toward oxidative type IIa muscle fibers. Note: despite the ERR name, these receptors do not bind estrogen.