SLU-PP-332

Verified against PubChem PUG-REST lookup by name returned CID 5338394 with molecular formula C18H14N2O2, molecular weight 290.3 and IUPAC name 4-hydroxy-N-[(E)-naphthalen-2-ylmethylideneamino]benzamide. The PubChem synonym list for that CID confirms CAS 303760-60-3 and the identifiers SR9861, CHEMBL4208749 and ERR pan-Agonist 332. Sequence is null because the compound is not a peptide. Fields marked “not verified” are ones we could not confirm against a primary chemical database — we leave them blank rather than guess.

Identity and what the molecule is

SLU-PP-332 is 4-hydroxy-N′-(naphthalen-2-ylmethylene)benzohydrazide, an acylhydrazone built from a 4-hydroxybenzohydrazide head and a 2-naphthaldehyde tail. PubChem lists it as CID 5338394 with CAS registry number 303760-60-3, molecular formula C18H14N2O2 and molecular weight 290.3. It also carries the identifiers SR9861 and CHEMBL4208749. At 290 daltons with a single rotatable imine linkage, it is a small molecule, not a peptide, and none of the handling conventions that apply to lyophilised peptides apply to it.

The compound came out of a rational design effort at Saint Louis University and Washington University. Billon and colleagues started from GSK4716, an agonist selective for ERRβ and ERRγ, and modified the scaffold to add ERRα activity — specifically by introducing a naphthalene group predicted to make a π-stacking interaction with Phe328 in ERRα, a position occupied by alanine in the β and γ isoforms. That is the structural basis of the ERRα selectivity the compound displays, and it was designed in rather than discovered by screening.

Receptor pharmacology as measured

The estrogen-related receptors are orphan nuclear receptors, homologous to the estrogen receptors but not bound by estrogens. They have strong constitutive transcriptional activity, and the standard readout for an agonist is a cell-based cotransfection reporter assay rather than a binding displacement assay.

In the original 2023 characterisation, Billon and colleagues reported potency in a full-length ERR cotransfection reporter assay in HEK293 cells: EC50 of 98 nM at ERRα, 230 nM at ERRβ and 430 nM at ERRγ. That corresponds to 4.4-fold selectivity for ERRα over ERRγ and 2.3-fold over ERRβ. The comparator GSK4716 was above 5000 nM at both ERRα and ERRβ in the same assay.

A 2026 structure-activity study from the same group reported different absolute values in a cotransfection system using an ERRE reporter with a One-Glo luciferase readout: EC50 of 0.22 μM at ERRα and 0.59 μM at ERRγ. Both papers place ERRα first, but the absolute potencies differ roughly two-fold between assay generations. Any single quoted EC50 for this compound is assay-specific, and comparisons across papers that do not state the assay are not meaningful.

Mechanistically, the compound is described as binding the ERR ligand-binding domain and promoting recruitment of the coactivators PGC-1α and PGC-1β.

What the mouse studies did and did not do

Two rodent papers carry almost all of the in vivo evidence, and both used the same delivery route. In the 2023 paper, Billon and colleagues gave male C57BL/6J mice 30 mg/kg by intraperitoneal injection and measured concentrations of roughly 0.6 μM in skeletal muscle and 0.2 μM in plasma at two hours. For the endurance work, six male C57BL/6J mice per group aged twelve weeks received 50 mg/kg intraperitoneally for six days before treadmill testing to exhaustion; the treated animals ran approximately 70% longer and 45% further than vehicle-treated animals. Vehicle was 10% Tween, 10% DMSO and 80% PBS.

In the 2024 metabolic syndrome paper, twenty-week-old male C57BL6/J mice maintained on a high-fat diet received 50 mg/kg intraperitoneally twice daily for 28 days, with 8 to 10 animals per group. Vehicle-treated animals gained approximately 5 g of fat mass over the period while treated animals gained under 0.5 g, and treated animals weighed approximately 12% less at the end. Fatty acid oxidation was reported as 25% higher than vehicle. In the ob/ob arm, dosing was shortened to 12 days because of reduced tolerance.

Every published in vivo figure for this compound comes from intraperitoneal injection in male mice. No study administered it by any other route.

The exercise-mimetic framing and what it rests on

The phrase 'exercise mimetic' comes from a specific and narrow comparison. Billon and colleagues gave three-month-old male C57BL/6J mice a single 50 mg/kg intraperitoneal dose and compared the differentially expressed genes in gastrocnemius and quadriceps muscle against a published dataset from mice subjected to 20 minutes of treadmill running. The overlap between the two gene sets was statistically significant. That is a transcriptional resemblance measured in mouse muscle at one to six hours after a single dose.

The label does not rest on any measurement of caloric expenditure equivalence, training adaptation over time, or comparison against a defined quantity of human exercise. The compound was also reported to increase type IIa oxidative fibres after 15 days of dosing and to raise maximum mitochondrial respiration in proliferating C2C12 myoblasts treated for 24 hours.

A separate line of work applied the compound to the aging mouse kidney. Wang and colleagues treated 21-month-old mice with an eight-week pan-ERR agonist course and reported reversal of age-related albuminuria, podocyte loss and mitochondrial changes, implicating cGAS-STING and STAT3 signalling. The estrogen-related receptors were also found to be decreased in aging human and mouse kidney and preserved in mice on lifelong caloric restriction, which is the basis for describing the compound as a caloric-restriction mimetic in that context.

The absence of human data

ClinicalTrials.gov was searched on 17 August 2026 for SLU-PP-332 by intervention name and by free-text term. It returned zero registered studies. A broader search for estrogen-related receptor agonists as exercise mimetics also returned zero. There is no phase 1 trial, no registered safety study, and no human pharmacokinetic dataset for this compound or, as far as the registry shows, for any ERR agonist in this class.

The 2026 structure-activity paper, which is the most recent work on the scaffold and comes from the group that made it, reports no human or clinical data. Its stated purpose is to define design principles for next-generation ERR agonists — that is, the compound is still positioned in the literature as a chemical probe and a starting scaffold, not as a candidate that has entered development.

The toxicology that exists is limited to what the 2023 paper recorded incidentally: no overt toxicity, normal complete blood count and electrolytes, and no significant change in serum creatine kinase in mice given 50 mg/kg twice daily intraperitoneally for ten days. Ten days of dosing in male mice of one strain is the extent of the published safety characterisation.

What is not known

There is no human data of any kind. No trial has been registered, so nothing is known about absorption, distribution, half-life, metabolism or elimination in humans by any route. Oral bioavailability is unmeasured in every species, which matters because oral delivery is the form most often supplied while injection is the only route the published pharmacology used. Chronic toxicity is uncharacterised: the longest published dosing interval is 28 days in mice, and the only safety panel reported covers ten days. Every in vivo study used male mice of a single strain, so nothing is known about effects in females, in other strains, or across species. Because the estrogen-related receptors regulate transcriptional programmes in heart, kidney, liver, brown adipose tissue and bone as well as skeletal muscle, and because the compound is a pan-agonist that engages all three isoforms, off-target tissue consequences of sustained systemic ERR activation have not been mapped. Reproductive, developmental and carcinogenicity studies have not been published. Whether the transcriptional overlap with acute exercise translates into any durable physiological adaptation, in mice or otherwise, has not been tested beyond the endurance and body-composition endpoints described above.

Questions