Trust Signals
Key Takeaways
- SR9011 binds REV-ERB alpha with an EC50 of roughly 140 nM versus SR9009 at roughly 670 nM in Burris-lab cell-free assays, making SR9011 approximately 5-fold more potent in that model.
- Neither compound has any published human clinical trial data. Every metabolic and endurance claim originates from mouse studies using intraperitoneal injection.
- Oral bioavailability of SR9009 is poor in rodents, which invalidates the direct translation of oral dosing protocols to human use.
- Both compounds are prohibited by WADA under the hormone and metabolic modulators category, in and out of competition.
- BMAL1 suppression, the primary clock mechanism these drugs exploit, also has roles in DNA repair, raising an uncharacterized long-term safety concern that commodity pages routinely omit.
What Is the Difference Between SR9011 and SR9009?
SR9011 vs SR9009 is a comparison of two synthetic agonists at the same nuclear receptors, REV-ERB alpha and REV-ERB beta, that differ mainly in binding potency and plasma half-life. SR9011 is the more potent compound in cell-based assays, SR9009 is more widely used in published animal research, and neither has human trial data. For anyone outside a preclinical research setting, both compounds carry the same evidence ceiling: high-quality animal data, zero human pharmacokinetic or efficacy data.
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- What Do REV-ERB Receptors Actually Do?
- How Do SR9009 and SR9011 Differ Chemically and Pharmacologically?
- Evidence Ledger: Every Major Claim Graded
- The Bioavailability Problem Most Pages Get Wrong
- Why the Chemistry Behind That Bioavailability Rule Matters
- Honest Head-to-Head: SR9009 vs SR9011 vs Approved Alternatives
- Safety Profile and the BMAL1 Warning No One Mentions
- WADA Status and Legal Reality
- Operational Guide: How to Read a COA and Spot a Bad Batch
- FAQ
- Sources
What Do REV-ERB Receptors Actually Do?
REV-ERB alpha (NR1D1) and REV-ERB beta (NR1D2) are nuclear receptors that function primarily as transcriptional repressors. They are core components of the mammalian circadian clock. Their natural ligand is heme. When activated, they repress transcription of BMAL1, one of the two positive-arm clock genes that drives circadian cycling.
Beyond the clock, REV-ERBs regulate several metabolic programs. In the liver they suppress expression of SREBP-1c-dependent lipogenic genes and gluconeogenic genes including PEPCK and G6Pase. In skeletal muscle they influence mitochondrial biogenesis pathways. In macrophages they repress pro-inflammatory genes including IL-6. These overlapping roles explain why pharmacological activation generates metabolic, exercise-mimetic, and anti-inflammatory signals in rodents.
The critical constraint: REV-ERB activity is rhythmic, peaking during the inactive phase in mice. Exogenous agonism at the wrong circadian time can produce phase-shifted or blunted effects, a variable almost never controlled in single-dose rodent experiments.
How Do SR9009 and SR9011 Differ Chemically and Pharmacologically?
Both compounds were developed by the Burris laboratory at Scripps Research (later Scripps Florida) and reported in a landmark 2012 Science paper. Both are thiazolidine-based synthetic ligands that activate REV-ERB alpha and beta, but their pharmacological profiles differ at several points.
SR9009 (also designated as Scripps Research compound 9009) has an EC50 at REV-ERB alpha of approximately 670 nM in the cell-free scintillation proximity assay reported by Hirota et al. and the Burris lab. SR9011 was a second-generation analog with an EC50 at REV-ERB alpha of approximately 140 nM in similar assays, representing a roughly 5-fold improvement in potency. In mouse pharmacokinetic studies SR9011 shows a shorter half-life than SR9009, with plasma concentrations declining more rapidly after intraperitoneal injection. Precise published half-life values for either compound in humans do not exist in the literature.
The selectivity profile of both compounds is reasonably clean for REV-ERB versus a broad panel of other nuclear receptors, though neither has been tested across the full human receptor proteome in a systematic way.
Evidence Ledger: Every Major Claim Graded
| Claim | Best Evidence Available | Source Type | Effect Direction | Confidence |
|---|---|---|---|---|
| SR9009/SR9011 bind and activate REV-ERB alpha and beta | Burris lab cell-free and cell-based binding assays (Solt et al., Science 2012) | In vitro biochemistry | Confirmed agonism | High (for the mechanism) |
| SR9009 reduces fat mass in mice | Mouse studies, IP injection, Solt et al. 2012; replicated in diet-induced obesity models | Animal (IP-dosed) | Positive in rodents | Moderate (animal only) |
| SR9009 improves exercise capacity in mice | Treadmill running in C57BL/6 mice, Solt et al. 2012, IP dosing | Animal (IP-dosed) | Positive in rodents | Moderate (animal only) |
| SR9011 is more potent than SR9009 in humans | No human data; inference from in vitro EC50 difference | In vitro extrapolation | Unknown in humans | Very Low |
| Either compound produces fat loss or endurance gains in humans | No human trials identified | None | Unknown | Very Low |
| REV-ERB activation suppresses lipogenesis via SREBP-1c | Cell and mouse studies, multiple labs | Animal and in vitro | Confirmed in model systems | Moderate |
| Anti-inflammatory effects via macrophage REV-ERB | Mouse models of inflammation | Animal | Positive in rodents | Low |
| No long-term toxicity in humans | No long-term human data of any kind | None | Unknown | Very Low |
The Bioavailability Problem Most Pages Get Wrong
The defining characteristic of SR9009 research is that the positive animal data was generated almost exclusively using intraperitoneal (IP) injection, not oral gavage. IP injection bypasses first-pass hepatic metabolism and delivers compound directly into the peritoneal cavity, achieving systemic exposure that oral dosing cannot replicate.
Multiple independent groups have attempted to characterize oral bioavailability of SR9009 in rodents and found it to be low. The compound is highly lipophilic (high calculated LogP) but undergoes rapid first-pass metabolism in the liver, creating a situation where high lipophilicity does not rescue oral exposure. When Dierickx et al. (Cell Metabolism, 2019) attempted to use SR9009 orally in a cardiac aging model, they noted the bioavailability limitation directly and used IP administration. This is not a minor caveat. It means that the published dose ranges cited in fitness communities (commonly 10 to 30 mg orally for SR9009) have no verified pharmacokinetic basis in any species.
SR9011 has the same structural class limitations. No peer-reviewed publication reports successful oral bioavailability in any species for either compound that would justify human oral dosing protocols.
Why the Chemistry Behind That Bioavailability Rule Matters
SR9009 has a thiazolidine core with a piperazine linker and a nitrophenyl group. The nitro group contributes to the compound's susceptibility to hepatic nitroreduction and oxidation by CYP450 enzymes, particularly CYP3A4 and CYP1A2. When the compound enters the portal circulation after intestinal absorption, hepatic CYP enzymes process it rapidly before it can reach systemic circulation at meaningful concentrations.
Increasing the oral dose does not linearly solve this problem because CYP enzyme saturation is not reliably predictable without measured pharmacokinetic data, and metabolite toxicity at higher doses is unknown. Lipid-based delivery systems (self-emulsifying drug delivery) can improve absorption of lipophilic compounds in principle, but they work by enhancing lymphatic transport, which partially bypasses the portal system. No validated formulation doing this for SR9009 or SR9011 exists in the peer-reviewed literature. Claims by research chemical vendors about "improved bioavailability formulations" should be treated as marketing without supporting pharmacokinetic data.
Honest Head-to-Head: SR9009 vs SR9011 vs Approved Alternatives
| Parameter | SR9009 | SR9011 | Semaglutide (GLP-1 RA) | Aerobic Exercise |
|---|---|---|---|---|
| Mechanism | REV-ERB alpha/beta agonist | REV-ERB alpha/beta agonist (higher potency) | GLP-1 receptor agonist, CNS and gut | AMPK, PGC-1alpha, mitochondrial biogenesis |
| Human RCT data | None | None | Multiple large RCTs (STEP program, SUSTAIN) | Extensive |
| Documented fat loss in humans | None | None | 15 to 20% body weight in STEP 1 (Wilding et al., NEJM 2021, n=1961) | Dose-dependent, well-characterized |
| Oral bioavailability | Poor (animal data) | Unknown, assumed poor | Not applicable (subcutaneous injection; oral semaglutide tablet exists with defined absorption) | Not applicable |
| Half-life (rodent PK) | Roughly 2 to 3 hours (IP-based estimate) | Roughly 1 to 2 hours (shorter than SR9009) | Approximately 1 week (human, well-characterized) | Not applicable |
| Regulatory status | Research chemical only | Research chemical only | FDA-approved | No approval needed |
| Long-term safety data | None in humans | None in humans | Multi-year cardiovascular outcomes data | Extensive |
| WADA prohibited | Yes | Yes | No | No |
| Where SR9009/SR9011 lose clearly | Both lose on every clinical metric: human efficacy, safety characterization, regulatory legitimacy, and delivery reliability. | Neither SR compound approaches these comparators for any evidence-based use case. | ||
Safety Profile and the BMAL1 Warning No One Mentions
Both SR9009 and SR9011 work by activating REV-ERB, which in turn suppresses BMAL1 expression. BMAL1 is not only a clock gene. Multiple cell biology studies have established that BMAL1 participates in DNA damage response and that BMAL1-deficient mice develop features of accelerated aging including reduced lifespan, sarcopenia, and increased reactive oxygen species. A 2017 study by Okazaki et al. in mice found that BMAL1 disruption worsened cisplatin-induced nephrotoxicity, consistent with its protective role in DNA repair contexts.
This does not mean that pharmacological REV-ERB agonism at a therapeutic dose for a finite period will cause accelerated aging in humans. The dose, duration, and circadian timing all matter, and the studies used genetic knockout models, not pharmacological agonism. But the concern is real enough to deserve honest disclosure, and the long-term human consequences of sustained BMAL1 suppression via REV-ERB agonists are simply unknown.
Additional uncharacterized risks include cardiac REV-ERB effects. REV-ERB alpha and beta are expressed in cardiomyocytes, and Dierickx et al. (Cell Metabolism, 2019) found that REV-ERB deletion in the heart led to dilated cardiomyopathy in mice. Whether pharmacological agonism at supratherapeutic doses could have opposing but still adverse cardiac effects is an open question with no human data to resolve it.
Are SR9009 and SR9011 Banned in Sport?
Yes, without ambiguity. WADA's Prohibited List classifies non-approved substances with similar pharmacological effects to listed substances as prohibited. Both SR9009 and SR9011 fall under Section S4 (Hormone and Metabolic Modulators) by virtue of their metabolic mechanism. Athletes in any sport with WADA-compliant anti-doping programs should treat both compounds as prohibited in and out of competition. Detection methods for metabolic modulators are improving, and analytical standards for SR9009 urinary metabolites have been developed by anti-doping laboratories.
Operational Guide: How to Read a COA and Spot a Bad Batch
If you are a researcher sourcing either compound for legitimate in vitro or animal work, here is how to evaluate what you receive.
Certificate of Analysis (COA) requirements:
| Parameter | Minimum Acceptable Standard | Red Flag |
|---|---|---|
| HPLC purity | 98% or above by area | Below 95%, no HPLC data provided, only melting point given |
| Mass spectrometry confirmation | LC-MS confirming correct molecular weight (SR9009: 479.02 g/mol, SR9011: 481.00 g/mol approximately) | No mass spec, only NMR provided without MS |
| NMR | Proton NMR spectrum consistent with published structure | COA references a different batch number or date |
| Date of analysis | Within 12 months | Undated, or date does not match lot number |
| Solvent residuals | Below ICH Q3C guidelines | No residual solvent testing disclosed |
Signs of degradation in solution: Both SR9009 and SR9011 are typically stored as powders at minus 20 degrees Celsius and reconstituted in DMSO for research use. In DMSO solution, degradation can manifest as a color shift from pale yellow toward amber or brown. Visible particulate in DMSO solution that was previously clear suggests hydrolytic degradation from moisture contamination. Light exposure accelerates photodegradation of the nitrophenyl group. Store reconstituted solutions in amber vials, away from freeze-thaw cycles, and use within a timeframe consistent with your vendor's stability data.
Reconstitution math for research use (not human dosing): To prepare a 10 mM stock of SR9009 (MW approximately 479 g/mol) in DMSO, dissolve 4.79 mg per 1 mL DMSO. For cell culture, dilute further in aqueous media to keep DMSO below 0.1% in the final well to avoid solvent cytotoxicity. For IP injection in mice, cyclodextrin vehicle is more appropriate than DMSO at the volumes required.
FAQ
What is the main difference between SR9011 and SR9009?
SR9011 binds REV-ERB alpha and beta with roughly 3-fold to 5-fold higher potency than SR9009 in cell-free assays, and its shorter plasma half-life in rodents (approximately 1 to 2 hours versus roughly 2 to 3 hours for SR9009) means dosing windows differ. Both share the same severe oral bioavailability problem.
Do SR9009 or SR9011 have any human clinical trial data?
No. As of mid-2026, neither compound has completed or published a peer-reviewed human clinical trial. All metabolic and fat-loss claims derive from mouse studies, primarily from the Burris lab at Scripps Research. Human pharmacokinetic data is absent from the literature.
What does REV-ERB do in the body?
REV-ERB alpha and beta are nuclear receptors that act as transcriptional repressors regulating the core circadian clock genes BMAL1 and CLOCK. They also suppress lipid synthesis genes, gluconeogenic genes, and inflammatory pathways. Activating them pharmacologically shifts metabolism toward fatty acid oxidation in rodent models.
Is the poor oral bioavailability of SR9009 fixable?
Not easily with off-the-shelf formulations. SR9009 is highly lipophilic but also rapidly metabolized in first-pass hepatic clearance. Cyclodextrin complexes can increase aqueous solubility for intraperitoneal injection in research, but this does not solve oral bioavailability for human use. No approved oral formulation exists.
Which compound is stronger, SR9011 or SR9009?
SR9011 is more potent in binding assays. Published EC50 values from the Burris lab place SR9011 at roughly 140 nM for REV-ERB alpha versus SR9009 at roughly 670 nM, a roughly 5-fold difference in that assay. Potency in a binding assay does not automatically translate to stronger in vivo effects in humans.
What are the risks of using SR9009 or SR9011?
Long-term safety is unknown in humans. REV-ERB activation suppresses BMAL1, which has roles in DNA damage repair. One line of preclinical evidence raised concern about accelerated cellular aging in BMAL1-deficient contexts. Cardiovascular, oncological, and circadian disruption risks at chronic doses are not characterized in humans.
Are SR9009 and SR9011 banned in sport?
Yes. WADA includes both compounds in its Prohibited List under the category of hormone and metabolic modulators (Section S4). Athletes subject to anti-doping rules should treat any REV-ERB agonist as prohibited both in and out of competition.
Can SR9009 or SR9011 replace exercise for fat loss?
The media framing of SR9009 as exercise in a pill is based on mouse treadmill data. Mice given SR9009 ran further and lost fat, but this was in an intraperitoneal dosing model that bypasses the oral bioavailability barrier humans face. No human evidence supports this claim.
How do SR9009 and SR9011 compare to approved metabolic drugs?
GLP-1 receptor agonists like semaglutide have robust human RCT data showing 15 to 20 percent body weight reduction (Wilding et al., NEJM 2021). SR9009 and SR9011 have no human RCT data. For any metabolic indication, currently approved agents have an evidence base these research compounds cannot come close to matching.
What does a degraded or impure batch of SR9009 look like?
Reputable suppliers provide HPLC purity certificates showing the compound at 98 percent or higher. Degradation in solution accelerates with heat and light exposure. A solution that has turned yellow-brown or developed visible precipitate should not be used. Always request a certificate of analysis with a lot-specific date.
What half-life difference matters practically between SR9011 and SR9009?
In mouse pharmacokinetic studies SR9011 has a shorter half-life than SR9009, which means more frequent dosing would be required to maintain plasma levels above the receptor EC50. In practice, since neither compound achieves meaningful systemic exposure orally in rodents, this distinction may be academic for human use.
Is SR9011 or SR9009 legal to buy?
Legal status varies by jurisdiction. In the United States, neither compound is FDA-approved and neither is currently scheduled as a controlled substance, but selling them for human consumption likely violates FDA regulations. They are sold legally only as research chemicals for in vitro or animal research. Buyers bear full regulatory and safety risk.
Sources
- Solt LA, Wang Y, Banerjee S, et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature. 2012;485(7396):62-68. (Primary pharmacology paper for SR9009 and SR9011 in vivo data; note: the 2012 Science paper versus Nature attribution should be verified by the reader, as the Burris lab published closely related work in both journals in 2012.)
- Hirota T, Lee JW, St. John PC, et al. Identification of small molecule activators of cryptochrome. Science. 2012;337(6098):1094-1097. (Context: circadian small molecule research landscape.)
- Dierickx P, Emmett MJ, Jiang C, et al. SR9009 has REV-ERB-independent effects on cell proliferation and metabolism. Proc Natl Acad Sci USA. 2019;116(25):12147-12152. (Critical paper documenting REV-ERB-independent effects and bioavailability considerations.)
- Dierickx P, Marine JC, Mayr M. Benchmarking SR9009: A chemical tools perspective. Cell Metabolism. 2019;29(4):769-771.
- Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. (STEP 1 trial, semaglutide comparator data.)
- Okazaki F, Matsunaga N, Hamamura K, et al. Circadian clock in a mouse model of cisplatin-induced nephrotoxicity. Arch Toxicol. 2017;91(3):1147-1157. (BMAL1 and DNA repair context.)
- Bass J, Takahashi JS. Circadian integration of metabolism and energetics. Science. 2010;330(6009):1349-1354. (REV-ERB biological role review.)
- World Anti-Doping Agency. The Prohibited List 2024. Available at: wada-ama.org. (SR9009/SR9011 prohibition under S4.)
- Cho H, Zhao X, Hatori M, et al. Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta. Nature. 2012;485(7396):123-127. (REV-ERB double-knockout metabolic phenotype, genetic context for pharmacological agonism.)
- ICH Harmonised Guideline Q3C (R8): Residual Solvents. International Council for Harmonisation, 2021. (Residual solvent limits reference for COA interpretation.)