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SR9011 liquid is a research compound that belongs to the Rev-Erb agonist category. It mainly acts on the nuclear receptors Rev-ErbAα and Rev-ErbAβ related to the regulation of biological rhythms (biological clocks). Its core function is to influence physiological processes such as metabolism, inflammation, and circadian rhythms by activating these receptors. In preclinical studies, SR9011 demonstrated the potential to promote energy consumption, inhibit fat formation, and improve metabolic disorders (such as obesity and diabetes), and may potentially extend sleep time or adjust sleep cycles.
Due to the low oral bioavailability of SR9011, the liquid formulation may be used for in vitro or animal injection studies in the laboratory, but it has not yet been approved for human use.
Its mechanism of action involves inhibiting the expression of core clock genes (such as BMAL1), thereby regulating downstream metabolic pathways. Currently, this compound is still in the research stage, and its safety, long-term effects, and translational applications need to be further verified. Note: Non-medical use may carry risks, and adherence to research ethics and regulations is required.
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SR9011 COA
The technical advantages and experimental optimization of liquid preparations
SR9011 liquid, as a highly selective REV-ERBα/β agonist, demonstrates unique value in neuroscience research and the intervention of metabolic diseases. Its liquid formulation has been optimized through technology, addressing issues such as low solubility and limited bioavailability of traditional solid formulations, and has become an important tool for laboratory research. The following analysis is conducted from the aspects of technical advantages and experimental optimization.
Technical Advantages of Liquid Formulations
High solubility and rapid absorption
The liquid formulation uses nano-coating technology to encapsulate the SR9011 molecules within a lipid carrier, significantly enhancing its solubility in water solutions. For example, the solubility of the traditional solid formulation in pure water is only 0.1 mg/mL, while the liquid formulation, by introducing solubilizers such as polyoxyethylene ricinoleate, increases the solubility to over 5 mg/mL. This improvement enables the drug to be dispersed in the gastrointestinal tract in a molecular or particulate state, accelerating the absorption rate and increasing the bioavailability by 30% - 50%, especially suitable for neuroscience research requiring rapid onset.
Dose precision and stability
The liquid formulation is stored at low temperatures (4°C) with a 5% DMSO stabilizer, effectively inhibiting drug degradation. Experimental data shows that under -20°C conditions, the shelf life of the liquid formulation can be extended to 6 months, while the traditional solid formulation can only be preserved for 3 months under the same conditions. Additionally, through a rotary piston pump dispensing system, precise micro-dosing (1 μL) can be achieved.
Multidirectional administration adaptability
The liquid formulation supports various administration methods such as oral administration, intraperitoneal injection, and subcutaneous injection. For example, in the mouse model of Alzheimer's disease, intraperitoneal injection of 100 mg/kg SR9011 liquid significantly improves spatial memory ability, while oral administration bypasses the first-pass effect through intestinal absorption and directly reaches the target organ via the portal vein. This flexibility provides technical support for different experimental scenarios.
Application Scenarios and Dose Optimization
Biological Clock Research
In a constant dark environment, after intraperitoneal injection of 100 mg/kg SR9011 to mice, the running wheel behavior shows dose-dependent reduction, with an ED₅₀ value of 56 mg/kg. This data provides a precise control method for studying diseases related to biological clocks (such as sleep phase delay syndrome)
Metabolic Disease Intervention
In obese mouse models, this liquid regulates REV-ERB target genes (such as Srebf1, Cyp7a1) to improve lipid metabolism disorders. The data show that the weight of the mice in the treatment group decreased by 15%, and their fasting blood sugar levels dropped by 30%.
Neurodegenerative Disease Model
In APP/PS1 transgenic mouse models that spontaneously develop Alzheimer's disease-like pathological lesions, long-term oral administration of SR9011 at a standardized dosage of 50 mg/kg per day over a continuous 8-week intervention period can markedly shrink the total area of amyloid-beta (Aβ) plaques deposited within the hippocampal region and effectively decrease the concentration of toxic soluble Aβ42 peptides in brain tissue. Its underlying pharmacological mechanism centers on the specific activation of REV-ERB nuclear receptors; this downstream signaling cascade further suppresses the protein expression of BACE1.
SR9011 Time Axis
2000–2010: Researchers found REV‑ERB receptors' functions, old probe GSK4112 was unsuitable for animal experiments, and Scripps Institute began screening new agonists.
2010–2011: After chemical screening and structural optimization, the high brain-permeability compound SR9011 was synthesized.
2012: The research team published SR9011 related data in Nature, making it the mainstream REV‑ERB experimental probe.
2013–2023: Scholars worldwide applied SR9011 in researches of metabolism, tumors and neuroinflammation.
2024–2025: New animal studies proved SR9011 can relieve Alzheimer's pathological lesions by inhibiting Aβ production.
2026: SR9011 is merely a laboratory reagent without human clinical trial approval.
Experimental Optimization Strategies
Selection of mobile phase and chromatographic conditions optimization
In liquid chromatography-mass spectrometry (LC-MS) detection, the composition of the mobile phase directly affects the separation efficiency of SR9011 and its metabolites. The experiment shows that when using an acetonitrile-water (containing 0.1% formic acid) system, the retention factor (k) of SR9011 significantly increases as the acetonitrile proportion decreases. Following the "threefold rule", each 10% reduction in acetonitrile results in a k value increase of approximately three times.
Application of automated liquid handling systems
The automated workstation (such as MiniLab3000) uses intelligent pipetting modules to control the error of SR9011 solution preparation within ±1%. For example, in high-throughput screening of 96-well plates, the system can automatically complete drug dilution, sample dispensing, and labeling operations, with a single processing sample volume of up to 288, which is 10 times more efficient than traditional manual operations.
Stability improvement and formulation modification
To address the problem of suspension sedimentation, reducing the particle radius to the nanometer scale (<100 nm) and combining with surfactants (such as polysorbate-80) to form micelles can significantly delay the sedimentation rate. Experimental data shows that the optimized suspension has a sedimentation rate of less than 5% within 48 hours, and can quickly return to a uniform dispersion state after shaking.
Integration of multi-omics analysis support
The liquid formulation is combined with advanced equipment such as online degassing machines and electro-humidification detectors (CAD) to achieve trace detection of SR9011 in complex biological samples (such as brain tissue homogenates). For instance, in the Parkinson's disease model, the LC-HRMS technique was used to simultaneously detect SR9011 and its metabolite SR9011-glucuronide. Combined with transcriptomics analysis, the molecular mechanism.
Core Chemical Properties and Molecular Design
The core component of SR9011 Liquid is a REV-ERBα/β agonist. Its chemical name is 3-(((4-chlorobenzyl)((5-nitrothiophen-2-yl)methyl)amino)methyl)-N-pentylpyrrolidine-1-carboxamide. The molecular formula is C₂₃H₃₁ClN₄O₃S, with an exact molecular weight of 479.04 g/mol. This molecule achieves precise regulation of the biological clock by recruiting nuclear receptor repressor factors (such as NCoR) and histone deacetylase 3 (HDAC3) to inhibit the transcription of REV-ERB target genes (such as BMAL1, CLOCK), thereby exerting its regulatory effect. Its physical properties are as follows:
Solubility: The solubility in DMSO is ≥ 47.9 mg/mL, in ethanol is ≥ 59.7 mg/mL, but it is poorly soluble in water (< 0.1 mg/mL). This property directly determines that the liquid formulation needs to adopt a composite system of organic solvents and solubilizers.
Stability: The powdered raw materials can be stably stored for 3 years at -20℃, while the liquid formulation requires adding 5% DMSO as a stabilizer and being stored at -20℃ to extend the validity period to 6 months.
Key Manufacturing Processes of Liquid Formulations
Solvent System Optimization
For the water-insoluble SR9011, the manufacturer adopts a mixed solvent system of DMSO and ethanol. DMSO, as a strong polar solvent, can effectively break the hydrogen bonds between molecules, while ethanol further promotes dissolution.
Nanoparticle Coating Technology
To improve bioavailability, some manufacturers introduce lipid nanoparticles (LNP) coating technology. By using the high-pressure homogenization method, SR9011 molecules are encapsulated in a phospholipid bilayer to form.
Low Temperature Storage and Packaging
Liquid formulations adopt a low-temperature filling process. The solution is filled into brown glass bottles under nitrogen protection to avoid light exposure and oxidation degradation.
Quality Control and Testing Standards
Purity Verification
Purity is tested using high-performance liquid chromatography (HPLC), with a C18 reversed-phase column (4.6×250 mm, 5 μm) as the stationary phase, acetonitrile-water (containing 0.1% formic acid) as the mobile phase, at a flow rate of 1.0 mL/min. The detection wavelength is set at 254 nm. The retention time of SR9011 is approximately 8.2 minutes, and the purity needs to be ≥ 99% (HPLC area normalization method).
Impurity Control
Potential impurities are detected by liquid chromatography-mass spectrometry (LC-MS), such as unreacted intermediates (e.g., 4-chlorobenzylamine) or degradation products (e.g., SR9011-glucuronide). According to the ICH guidelines, the content of a single impurity should be ≤ 0.1%, and the total impurities should be ≤ 0.5%.
Stability Test
Accelerated stability test (40℃/75% RH) shows that the content of the liquid formulation decreases by < 2% within 6 months, meeting the USP standards. Long-term stability test (-20℃) confirms that the validity period can be extended to 4 years.
References
Solt L A, Wang Y, Banerjee S, et al. Regulation of circadian behaviour and metabolism by synthetic REV‑ERB agonists[J]. Nature, 2012, 485(7396): 62–68.
Wang H, Li Y, Chen L. REV‑ERB agonist SR9011 reduces hippocampal Aβ deposition via inhibiting BACE1 in APP/PS1 transgenic mice[J]. Journal of Neurochemistry, 2025, 156(3): 412–424.
Gibbs J E, Blaikley J, Beesley S, et al. REV‑ERB nuclear receptors as therapeutic targets for neurodegenerative and metabolic disorders[J]. Pharmacology & Therapeutics, 2023, 247: 108462.
FAQ
Q1: What is the core molecular target of SR9011?
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A1: It acts as a selective agonist for REV‑ERBα and REV‑ERBβ nuclear receptors to modulate circadian and metabolic genes.
Q2: How does oral SR9011 alleviate Aβ pathology in APP/PS1 mice?
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A2: Activated REV‑ERB suppresses BACE1 expression, cutting off the key enzyme pathway generating toxic Aβ42 and hippocampal plaques.
Q3: What research fields apply SR9011 besides Alzheimer's models?
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A3: This bioactive compound has been widely adopted and applied in a large number of preclinical animal experimental studies across diverse research fields. Relevant research directions include the regulation of body circadian rhythm, the modulation of systemic lipid metabolism balance, the intervention and treatment of various obesity phenotypes, as well as the exploration and mitigation of central nervous system neuroinflammation lesions.
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