SLU-PP-332 (ERR agonist / "exercise mimetic")

Identity a small synthetic molecule (not a peptide) developed by rational drug design as an agonist of the estrogen-related receptors (ERRα, ERRβ, ERRγ) — orphan nuclear receptors that are master regulators of mitochondrial metabolism and the exercise-responsive gene program in muscle. By switching ERR on pharmacologically, SLU-PP-332 aims to reproduce the transcriptional signature of aerobic exercise in a pill — hence "exercise mimetic." ## Mechanism (as proposed) the estrogen-related receptors (ERRα/β/γ) are orphan nuclear receptors that act as master transcriptional regulators of mitochondrial biogenesis, oxidative metabolism, and the gene program muscle activates in response to aerobic exercise. SLU-PP-332 binds and activates all three ERR isoforms, transcriptionally switching on a broad set of fatty-acid-oxidation and mitochondrial genes — increasing oxidative (slow-twitch) muscle fibers, energy expenditure and endurance, and shifting fuel use toward fat. In effect it triggers an "acute aerobic exercise response" at the gene-expression level. The appeal is obvious (exercise's benefits without the exercise); the reality is that this is shown in mice, and the molecule's poor oral bioavailability limits how well it could even work as a human oral drug.