SLU-PP-332

What Is SLU-PP-332?

SLU-PP-332 is a synthetic small-molecule agonist that activates all three estrogen-related receptors (ERRα, ERRβ and ERRγ), with the highest potency for ERRα. Its 2023 discovery paper reported that it had pharmacokinetic properties sufficient for use as an in-vivo chemical tool^[1].

The ERRs are orphan nuclear receptors that regulate genes involved in mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation and the Krebs cycle, and they are essential for skeletal muscle adaptation to aerobic exercise^[2]. Because SLU-PP-332 switches on an acute aerobic exercise gene program, it is studied as an exercise mimetic^[1].

Despite being discussed alongside research peptides, SLU-PP-332 is not a peptide. A 2026 study describes it as a well-established exercise mimetic and widely used chemical probe for ERR activation^[3]. All published efficacy data come from cell and animal models.

Chemical Structure and Molecular Identity

SLU-PP-332 is an aryl acyl hydrazone with the molecular formula C18H14N2O2 and a molecular weight of 290.3 g/mol. PubChem lists it under CID 5338394 with CAS number 303760-60-3 and InChIKey RNZIMBFHRXYRLL-XDHOZWIPSA-N.

Structurally, it links a 4-hydroxybenzoyl group through a hydrazone (C=N-NH-C=O) bridge to a 2-naphthyl group, with the E configuration at the C=N double bond. Its chemical name is (E)-4-hydroxy-N’-(naphthalen-2-ylmethylene)benzohydrazide, and PubChem also lists the synonym ERR pan-agonist 332.

• Ring systems: a phenol ring and a naphthalene ring
• Hydrogen-bond donors / acceptors: 2 / 3 (PubChem computed)
• Computed XLogP: 3.7, indicating a fairly lipophilic molecule
• Rotatable bonds: 3

In human liver S9 incubations, metabolism occurred mainly on these two ring systems: hydroxylation of the naphthalene or phenolic rings, plus direct glucuronidation and sulfation of the parent compound^[4]. A 2026 structure-activity study was the first to systematically map which parts of the scaffold control ERRα and ERRγ agonism, ligand efficiency and physicochemical properties^[3].

Research History and Development

SLU-PP-332 was first reported in 2023 and was followed by mouse studies in obesity and heart failure, a second-generation analog, and doping-control analytics. The 2023 ACS Chemical Biology paper noted that designing compounds with ERRα agonist activity had been difficult and that few synthetic agonists could target ERRs in vivo^[1].

A 2024 study in Circulation described SLU-PP-332 and SLU-PP-915 as two structurally distinct pan-ERR agonists designed by a structure-based approach and tested them in a pressure-overload heart failure model^[5]. The same year, a study in obese mice examined its effects on metabolic syndrome^[6]. A 2026 paper reported that SLU-PP-332 lacks oral bioavailability, motivating characterization of the orally bioavailable SLU-PP-915^[2].

As interest grew, anti-doping laboratories began characterizing its metabolites^[7][4], and a 2026 systematic review covering 2020 to 2024 assessed pan-ERR agonists as exercise mimetics^[8]. That same year, the first comprehensive structure-activity analysis of the SLU-PP-332 scaffold combined chemical synthesis, cell-based assays, gene-expression profiling, docking and molecular dynamics simulations^[3].

Mechanisms Studied in Research

SLU-PP-332 acts by binding and activating ERR nuclear receptors, which switch on metabolic genes tied to mitochondrial function and fatty acid use. In a skeletal muscle cell line it increased mitochondrial function and cellular respiration, and in mice it induced an ERRα-specific acute aerobic exercise gene program^[1].

Isoform dependence differs by tissue

Downstream metabolic programs

In the heart, ERR agonists transcriptionally activated a broad set of metabolic genes, especially those for fatty acid metabolism and mitochondrial function, and increased mitochondrial oxidative capacity and fatty acid use in vitro and in vivo^[5]. The 2026 systematic review summarized the gene program as ERRα-dependent and including Ddit4 and Slc25a25^[8].

At the whole-body level, SLU-PP-332 mimicked exercise-induced benefits on metabolism in mice, including higher energy expenditure and fatty acid oxidation^[6]. The review also notes the shift toward type IIa fibers, which are oxidative-glycolytic and use a mix of fatty acids and glucose^[8].

Key Findings From Published Studies

Published findings on SLU-PP-332 are limited to mouse studies, cell culture and in-vitro metabolism work; no human trial has been reported. The main themes are endurance, obesity and metabolic syndrome, and heart failure.

Exercise capacity (mouse)

SLU-PP-332 increased type IIa oxidative skeletal muscle fibers and enhanced exercise endurance in mice^[1]. A 2026 study found SLU-PP-915 enhanced running distance and duration to a similar extent as SLU-PP-332 under matched experimental conditions^[2].

Obesity and metabolic syndrome (mouse)

In diet-induced obese and ob/ob mice, SLU-PP-332 increased energy expenditure and fatty acid oxidation, decreased fat mass accumulation, reduced obesity and improved insulin sensitivity^[6]. The 2026 systematic review reported reduced adiposity, improved glycemic control and higher basal energy expenditure in obesity models without evident toxicity, plus restored mitochondrial function and reduced inflammation in aging kidneys^[8].

Heart failure (mouse)

In a pressure overload-induced heart failure model, both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis and increased survival without affecting cardiac hypertrophy. Metabolomics showed substantial normalization of fatty acid, lipid, TCA cycle and oxidative phosphorylation metabolites after six weeks of pressure overload^[5].

Human cells and metabolism (in vitro)

• A 2025 pilot study treated primary myoblasts from the muscle of physically inactive women with SLU-PP-332 to assess metabolic and expression changes linked to ERR activation. At baseline, muscle from inactive women showed higher NOX4 and lower SIRT1, PGC-1α, ERRα and FNDC5 expression than muscle from active women^[9].
• With human liver S9 fractions and microsomes, one laboratory identified nine metabolites (six phase I, three phase II)^[7], while another, using S9 fractions, identified 22 hydroxylated, glucuronidated and sulfated metabolites^[4].

Because hydrazones like SLU-PP-332 can isomerize or hydrolyze, researchers confirm identity and purity with HPLC and mass-spectrometry certificates of analysis.

Because hydrazones like SLU-PP-332 can isomerize or hydrolyze, researchers confirm identity and purity with HPLC and mass-spectrometry certificates of analysis.

Regulatory and Research Status

SLU-PP-332 is not an FDA-approved drug and has not been tested in published human clinical trials. The 2026 systematic review of pan-ERR agonists concluded that clinical trials are needed to confirm efficacy and safety in humans^[8].

In sport, the World Anti-Doping Agency prohibits exercise mimetics and metabolic modulators, and doping-control laboratories have published in-vitro metabolite profiles of SLU-PP-332 to detect misuse^[4]. A separate 2026 analytical study described the compound as having doping potential and characterized it by high-resolution mass spectrometry^[7].

Development work has shifted partly toward analogs. The 2026 structure-activity study reported analogs with comparable or context-dependent transcriptional activity and improved ligand efficiency, solubility or metabolic stability, while describing SLU-PP-332 as a benchmark for ERR activation^[3]. Open questions include long-term safety, the balance of isoform effects across tissues, and whether mouse findings translate to other species.