GW-0742 vs Mirabegron (YM-178)

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.

Mirabegron selectively activates the human β3-adrenergic receptor with reported low-nanomolar potency (~22.4 nM EC50 for cAMP accumulation in vitro, label-corroborated) and approximately 500-fold lower activity at β1/β2 receptors. Clinically, β3-AR activation relaxes detrusor smooth muscle during bladder storage, increasing capacity without impairing voiding contractions. β3-AR is also expressed on human brown and beige adipose tissue, where agonism increases thermogenesis and metabolic rate—the basis for investigational metabolic studies.