AICAR vs SLU-PP-915

Metabolic

Metabolic

Research Only

Research Only

AICAR is taken into cells and phosphorylated to ZMP, an AMP-mimetic that allosterically activates AMPK (binding the γ-subunit CBS domains and protecting Thr172 from dephosphorylation). Because ZMP can reach millimolar levels, AICAR also has substantial AMPK-independent effects on other AMP-sensitive enzymes and nucleotide metabolism (Visnjic et al., 2021). In sedentary mice, 4 weeks of AICAR increased treadmill endurance ~44% (Narkar et al., Cell 2008).

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).

Not established in humans; engineered for improved metabolic stability and oral exposure relative to first-generation ERR agonists