Alagebrium (ALT-711) vs GW-0742

Metabolic

Metabolic

Research Only

Research Only

Proposed to chemically cleave alpha-dicarbonyl carbon–carbon bonds within certain advanced glycation end-product (AGE) protein crosslinks, releasing crosslinked collagen and proteins in vascular and myocardial tissue and thereby reducing tissue stiffness. Additional proposed activities include methylglyoxal scavenging and metal chelation (e.g., inhibition of copper-catalyzed ascorbate oxidation); whether in vivo effects arise from AGE-crosslink cleavage versus metal chelation is unresolved. There is no evidence it cleaves glucosepane, considered the most abundant AGE crosslink in human tissue, which limits confidence in crosslink-breaking as the sole explanation for observed effects.

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.