Overview

SR-9011 is a synthetic agonist of the nuclear receptors Rev-Erbα (NR1D1) and Rev-Erbβ (NR1D2), developed by Professor Thomas Burris at the Scripps Research Institute alongside its more widely known analog SR-9009 (Stenabolic). Rev-Erb receptors are core components of the circadian clock machinery that function as constitutive transcriptional repressors, rhythmically suppressing the expression of BMAL1 and other clock genes to maintain circadian oscillations. Beyond timekeeping, Rev-Erbs regulate a broad array of metabolic genes involved in lipid metabolism, glucose homeostasis, adipogenesis, and inflammatory responses. SR-9011 activates these receptors, amplifying their repressive transcriptional activity and producing pronounced metabolic effects that overlap with — and in some cases exceed — those of endurance exercise.

In preclinical studies, SR-9011 demonstrates robust effects on energy metabolism: it increases mitochondrial content and activity in skeletal muscle, enhances fatty acid oxidation, reduces fat mass without changes in food intake, improves glucose tolerance, and reduces plasma triglycerides and cholesterol. Mice treated with SR-9011 show approximately 50% increases in running endurance, reduced anxiety-like behavior, and improved wakefulness patterns. These effects are largely shared with SR-9009, though SR-9011 features structural modifications that improve its metabolic stability and oral bioavailability — key limitations of SR-9009, which has notoriously poor oral bioavailability (approximately 2%) due to extensive first-pass hepatic metabolism. SR-9011's improved pharmacokinetics make it a more practical tool compound for in vivo research.

SR-9011 remains a research chemical with no human clinical trials completed. Its circadian mechanism distinguishes it from other exercise mimetics like GW501516 (PPARδ agonist) and SLU-PP-332 (ERR agonist), offering a unique entry point into metabolic enhancement through clock gene modulation. Rev-Erb agonism also shows anti-inflammatory potential — SR-9011 suppresses IL-6, MCP-1, and other pro-inflammatory mediators in macrophages — and has demonstrated anticancer activity in glioblastoma and other malignancies, potentially by disrupting the circadian regulation that cancer cells exploit for survival. As with other potent metabolic research compounds, SR-9011 has attracted interest in bodybuilding and athletic performance communities despite the absence of human safety data, and it is banned by WADA under the S4 (hormone and metabolic modulator) category.

Mechanism of Action

SR-9011 is a synthetic small-molecule agonist of the nuclear receptors REV-ERBalpha (NR1D1) and REV-ERBbeta (NR1D2), key components of the mammalian circadian clock. These receptors function as transcriptional repressors, and when activated by SR-9011, they suppress expression of core clock genes including BMAL1 and CLOCK, as well as downstream metabolic target genes. By modulating circadian transcription, SR-9011 profoundly alters lipid metabolism, reducing lipogenesis and increasing fatty acid oxidation through repression of SREBP and activation of mitochondrial pathways.

SR-9011 enhances mitochondrial content and oxidative capacity in skeletal muscle, increasing energy expenditure and exercise endurance in animal models. It reduces fat mass without affecting lean mass, making it of interest as a potential exercise mimetic. The compound also modulates inflammatory responses through REV-ERB-mediated repression of NF-kB target genes in macrophages and microglia, reducing production of IL-6, TNF-alpha, and CCL2. In microglia specifically, SR-9011 shifts cellular metabolism from glycolysis toward oxidative phosphorylation, attenuating the pro-inflammatory M1 phenotype.

SR-9011 also regulates sleep architecture, increasing wakefulness and reducing REM and slow-wave sleep when administered during the rest phase. It has demonstrated anxiolytic-like effects in animal behavioral models. Unlike its close analog SR-9009, SR-9011 has somewhat improved oral bioavailability, though both compounds face significant pharmacokinetic challenges including rapid hepatic metabolism. SR-9011 remains primarily a research tool for studying circadian biology and REV-ERB pharmacology.

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Research

Safety Profile

Safety Profile: SR-9011

Common Side Effects

• Limited human clinical data; most information from animal studies and anecdotal user reports
• Reported sleep disturbances and altered circadian rhythm
• Gastrointestinal discomfort: nausea and appetite changes
• Headache and mild anxiety
• Wakefulness and difficulty sleeping (consistent with Rev-Erb agonist mechanism)

Serious Adverse Effects

• No FDA approval or human clinical trials: Safety profile is largely unknown
• Potential for circadian rhythm disruption with chronic use, affecting hormonal axes, metabolism, and immune function
• Possible hepatotoxicity (Rev-Erb receptors are involved in liver metabolism)
• Uncertain cardiovascular effects despite proposed cardioprotective mechanism
• Unknown long-term consequences of chronic Rev-Erb modulation on organ systems

Contraindications

• Pregnancy and lactation (unknown teratogenic potential)
• Liver disease (hepatic metabolism concerns)
• Sleep disorders (may exacerbate circadian disruption)
• Shift workers (already disrupted circadian biology may be further destabilized)
• Children and adolescents

Drug Interactions

• CYP450 substrates: Rev-Erb modulation affects circadian expression of hepatic CYP enzymes; unpredictable drug metabolism changes
• Sedatives and sleep aids: Opposing effects may reduce efficacy
• Hormonal therapies: Circadian disruption may alter hormone cycling and drug timing sensitivity
• Other metabolic modulators (GW501516, AICAR): Stacking research compounds multiplies unknown risks

Population-Specific Considerations

• Research compound only: Not approved for human use anywhere in the world; marketed in gray-market research chemical space
• Athletes: Potential performance-enhancing effects on endurance and fat metabolism; WADA status should be verified
• Bioavailability: Poor oral bioavailability is a known limitation; injectable formulations carry additional infection and dosing risks
• Risk-benefit: No established therapeutic indication; risks are poorly characterized relative to any potential benefit

Pharmacokinetic Profile