Compound description
What is SLU-PP-332
Mechanism of action. ERRs (estrogen-related receptors) are orphan nuclear receptors — despite the name, they are not regulated by estrogen. SLU-PP-332 is a non-selective pan-agonist of all three isoforms, with the highest affinity for ERRα (EC₅₀ = 98 nM; ERRβ 230 nM, ERRγ 430 nM). ERRα activation triggers the transcriptional program for mitochondrial biogenesis and fatty acid oxidation — the same program switched on by acute aerobic exercise (hence the "exercise mimetic" label); the in vitro effect has been shown in skeletal muscle cell lines (increased mitochondrial respiration).
Research profile. In mice, a single dose before testing increased running endurance (time and distance), and repeated dosing reproduced the acute genetic response to aerobic exercise in an ERRα-dependent manner. Across obesity models — diet-induced and genetic (ob/ob) — the compound raised energy expenditure and fatty acid oxidation, lowered fat mass (~25-30% over 28 days without exercise), and improved insulin sensitivity and glucose tolerance, with no change in food intake. In a pilot study on primary myoblasts from sedentary elderly women, the compound lowered the oxidative-stress marker NOX4 and raised SIRT1, PGC-1α, ERRα, FNDC5, Akt, and Bcl-2, reducing cellular senescence and promoting myotube formation. Detailed results with links to the primary sources are in the research table below.
Evidence base
All available research on SLU-PP-332
2020 chemical foundation: converting an ERRβ/γ agonist into a pan-agonist
Chemical foundation
Earlier work by the same team (Elgendy, Burris, and co-authors) that established the chemical principle of converting the ERRβ/γ-selective agonist GSK4716 into pan-agonists via modification of an aromatic substituent. This study laid the scaffold from which the same lab derived SLU-PP-332 itself three years later — the compound was not tested here; this is the methodological foundation, not a direct SLU-PP-332 study.
Compound discovery: EC₅₀ 98 nM at ERRα, +70% running endurance
Compound discovery
Optimizing the GSK4716 scaffold by replacing its isopropylphenyl group with a naphthalene ring gave a 50-fold gain in ERRα potency (EC₅₀ 98 nM vs. >5000 nM for GSK4716). In mice, a single dose before testing increased time to exhaustion by roughly 70% and distance by 45% versus control; the effect was ERRα-dependent (lost in mice with muscle-specific receptor knockout). No toxicity was observed with 10-day dosing.
Kidney protection in aged mice: reversed albuminuria and inflammation in 8 weeks
Kidney protection
In 21-month-old mice, 8 weeks of SLU-PP-332 treatment reversed the age-related rise in albuminuria, podocyte loss, mitochondrial dysfunction, and inflammatory cytokines in the kidney — an effect comparable to lifelong caloric restriction, mediated via the cGAS-STING-STAT pathway.
Heart failure: improved ejection fraction, less fibrosis
Cardiac protection
In a mouse model of pressure-overload heart failure (TAC), both ERR pan-agonists — SLU-PP-332 and SLU-PP-915 — significantly improved ejection fraction and reduced fibrosis without affecting cardiac hypertrophy. The effect was mainly mediated through ERRγ, with normalization of the cardiac fatty-acid and TCA/OXPHOS metabolomic profile.
Metabolic syndrome: higher energy expenditure, lower fat mass with no change in appetite
Metabolic syndrome
Across two independent obesity models — diet-induced and genetic (ob/ob) — SLU-PP-332 raised resting energy expenditure and fatty acid oxidation, lowered fat mass, and improved glucose tolerance and insulin sensitivity, with no change in food intake in either model.
Independent confirmation in human cells: less myoblast senescence in sedentary women
Independent confirmation
A pilot study by an independent Italian group (unaffiliated with the developing lab) using primary myoblasts derived from muscle biopsies of 20 women. In cells from sedentary donors, SLU-PP-332 lowered the oxidative-stress marker NOX4 and raised SIRT1, PGC-1α, ERRα, FNDC5, Akt, and Bcl-2, reducing cellular senescence and promoting myotube formation.
Doping control: 22 metabolites identified in human liver fractions
Doping control
An independent analytical study for anti-doping purposes identified 22 metabolites of SLU-PP-332 (5 monohydroxylated, 3 dihydroxylated, 4 reduced dihydroxylated, and other conjugated forms) — groundwork for future detection methods in sports drug testing.
Second independent doping-control study: 9 metabolites, compared with SLU-PP-915
Doping control
Independent of the previous study (a different lab — the German Sport University Cologne), this work identified 9 metabolites of SLU-PP-332 (6 Phase-I, 3 Phase-II) versus 7 metabolites of the structurally distinct pan-agonist SLU-PP-915 — the metabolite-count discrepancy between the two independent groups shows the metabolic map is still being refined.
2026 chemical optimization: first systematic SAR analysis of the scaffold
Chemical optimization
The first systematic structure-activity relationship (SAR) analysis of the SLU-PP-332 scaffold: a series of analogues was synthesized (BE5040, BE5049, BE5112, and others), several of which showed comparable or better efficacy with improved solubility and metabolic stability than the original compound — SLU-PP-332 remains the benchmark for ERR activation.
