Alagebrium (ALT-711) vs SLU-PP-915

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.

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).