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| Targets |
TRPV1 (vanilloid receptor 1). SB452533 is a competitive antagonist at the capsaicin binding site. pKb values: human TRPV1 pKb 7.7 (vs. capsaicin); pA2 = 8.01 from Schild analysis; pIC50 vs. pH-mediated activation = 7.0 (human TRPV1); rat TRPV1 pKb 7.7 (vs. capsaicin); rat dorsal root ganglion native receptor pKb 7.4; guinea pig TRPV1 pKb 7.5. [1].
SB452533 targets the Transient Receptor Potential Vanilloid 1 (TRPV1) channel, a non-selective cation channel that is activated by a variety of noxious stimuli including capsaicin, acid (low pH), and noxious heat. It acts as a competitive antagonist, binding to the TRPV1 channel and blocking its activation. In HEK293 cells expressing the cloned recombinant rat TRPV1 receptor, SB452533 demonstrates a strong antagonistic effect. Its activity is characterized by its ability to inhibit multiple modes of TRPV1 activation. |
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| ln Vitro |
In HEK293 cells, SB 452533 has a strong antagonistic effect on the cloned recombinant rat TRPV1 receptor, with a pKb of 7.7 and a pIC50 of 7.0 [1]. AMPK and CAMKK2 phosphorylation is decreased by SB-452533 [2].
In HEK293 cells expressing human TRPV1, SB452533 (1 μM) reversibly inhibited whole-cell currents evoked by 1 μM capsaicin and by low pH (pH 5.3) in patch clamp recordings (n=3) [1]. In rat dorsal root ganglion neurons, 1 μM SB452533 reversibly inhibited capsaicin-evoked native TRPV1 currents (n=4) [1]. In FLIPR Ca²⁺ assays using HEK293.TRPV1 cells, SB452533 (10-300 nM) concentration-dependently inhibited capsaicin-evoked Ca²⁺ entry. Schild analysis showed a competitive mechanism with pA2 = 8.01 [1]. In HEK293.TRPV1 cells, SB452533 (1 μM) reversibly inhibited noxious heat (50 °C)-evoked whole-cell currents by 93±2% (n=3) [1]. A quaternary methiodide salt of SB452533 (compound 21) showed moderate antagonist activity in FLIPR (pKb 7.0). In electrophysiology, when applied intracellularly at up to 100 μM it was inactive, but when applied extracellularly it fully blocked capsaicin-evoked responses, indicating that the binding site for this template is extracellularly accessible [1]. Intrinsic clearance in rat and human liver microsomes: rat >50 mL/min/g liver, human 41 mL/min/g liver (high clearance) [1]. In vitro, SB452533 is a potent antagonist at the TRPV1 receptor. Against capsaicin-induced activation, it exhibits a pKb of 7.7. It also inhibits noxious heat and acid-mediated receptor activation with a pIC50 of 7.0. Its binding affinity (pKi) at the recombinant human TRPV1 receptor is 6.22. Furthermore, in skeletal muscle (C2C12) cells, SB-452533 (at concentrations of 50, 100, 200, and 400 μM) dramatically diminishes capsaicin-induced phosphorylation of AMPK and CAMKK2. |
| ln Vivo |
SB-452533 reverses the effects of small doses of capsaicin (Cap; low dose 2 mg/kg) and greatly reduces bleomycin-induced lung fibrosis in mice [3].
In vivo, SB-452533 reverses the effects of small doses of capsaicin (2 mg/kg). In a mouse model, it has been shown to greatly reduce bleomycin-induced lung fibrosis. In a specific study using a BALB/c mouse pulmonary fibrosis model, SB-452533 was administered via daily subcutaneous injection at a dose of 2.5 mg/kg for 21 days to evaluate its effect. It also exhibits analgesic properties. |
| Enzyme Assay |
The primary in vitro assay for characterizing SB452533's antagonism involves assessing its ability to inhibit capsaicin, acid, and heat-induced activation of the TRPV1 channel. Functional assays typically use cell lines expressing the TRPV1 receptor, such as HEK293 cells, and measure intracellular calcium flux (e.g., using FLIPR) or electrophysiological changes. Radioligand binding assays may also be used to determine its affinity (pKi) for the receptor. One study describes an assay where human TRPV1 expressed in 1321N1 astrocytoma cells were plated and used for compound testing.
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| Cell Assay |
Western Blot Analysis[2]
Cell Types: Skeletal Muscle (C2C12) Cell Tested Concentrations: 0, 50, 100, 200 and 400 μM Incubation Duration: 30 minutes; then treated with 200 μM capsaicin for an additional 30 minutes. Experimental Results: Dramatically diminished capsaicin-induced AMPK and CAMKK2 phosphorylation. FLIPR Ca²⁺ assay for TRPV1 antagonism: Human TRPV1 stably expressed in 1321N1 cells (or HEK293 cells) was used. Cells were loaded with Fluo-3. Test compounds were preincubated, then capsaicin (agonist) was added to activate TRPV1. Fluorescence change (Ca²⁺ influx) was measured using a fluorescence imaging plate reader. Antagonist activity was expressed as pKb [1]. Whole-cell patch clamp electrophysiology: HEK293 cells expressing human TRPV1 or rat dorsal root ganglion neurons were used. TRPV1-mediated currents were evoked by 1 μM capsaicin, pH 5.3 buffer, or noxious heat (50 °C). SB452533 (1 μM) was co-applied. Reversibility was assessed. For the quaternary salt 21, intracellular application (inclusion in pipette solution, >4 min pre-application) versus extracellular application was compared [1]. Schild analysis: Concentration-response curves for capsaicin-evoked Ca²⁺ entry in HEK293.TRPV1 cells were generated in the presence of increasing concentrations of SB452533 (10-300 nM). Data were analyzed to determine pA2 value [1]. In vitro liver microsome clearance: Rat and human liver microsomes were used to determine intrinsic clearance rates (mL/min/g liver) [1]. In vitro cell-based assays for SB452533 often employ skeletal muscle C2C12 cells. In these assays, cells are treated with various concentrations of the compound (e.g., 0, 50, 100, 200, and 400 μM) for 30 minutes, followed by stimulation with capsaicin (e.g., 200 μM) for an additional 30 minutes. The readout typically involves assessing the phosphorylation state of downstream signaling proteins like AMPK and CAMKK2 via Western blot analysis, where SB-452533 treatment dramatically diminishes capsaicin-induced phosphorylation. |
| Animal Protocol |
Animal/Disease Models: BALB/c mouse pulmonary fibrosis model [3]
Doses: 2.5 mg/kg Route of Administration: Daily subcutaneous injection for 21 days Experimental Results: Effect of Cap (reduce bleomycin-induced pulmonary fibrosis ) in the presence of SB-452533. In vivo animal studies for SB452533 have been conducted using a BALB/c mouse model of pulmonary fibrosis. In this model, fibrosis is induced by bleomycin, and the effect of the compound is evaluated. SB-452533 is administered via daily subcutaneous injection at a dose of 2.5 mg/kg for 21 days. The primary endpoint is the reduction in bleomycin-induced lung fibrosis, which is assessed histologically and biochemically. |
| ADME/Pharmacokinetics |
ADME: In vitro intrinsic clearance in rat liver microsomes >50 mL/min/g liver; in human liver microsomes 41 mL/min/g liver. This high clearance makes SB452533 unsuitable for in vivo studies [1].
Specific pharmacokinetic (PK) data for SB452533, such as half-life and bioavailability, are not extensively detailed in the available literature. However, it is known that the compound has a high in vivo clearance rate. It served as a structural template for the clinical candidate SB-705498, which was developed to improve upon its PK profile. SB452533 has a calculated LogP of 4.682, indicating moderate lipophilicity. It is soluble in DMSO at high concentrations (e.g., ~100 mg/mL) and can be formulated for in vivo administration using solvents like DMSO, PEG300, Tween-80, and saline. |
| Toxicity/Toxicokinetics |
Toxicological data for SB452533 are primarily derived from its use as a research tool. Specific toxicity profiles, such as LD50 values, are not prominently reported in standard research summaries. As with many TRPV1 antagonists, potential side effects could be related to its mechanism of action, which may include effects on thermoregulation and pain perception. The compound is a small molecule with a molecular weight of 376.29 g/mol and a XlogP of 4.4, suggesting potential for metabolic clearance. It is classified as a research-grade compound and is not intended for human therapeutic use.
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| References |
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| Additional Infomation |
SB452533 (SB-452533) is a potent, competitive TRPV1 antagonist that blocks capsaicin, acid (pH 5.3), and noxious heat (50 °C)-mediated activation. It is equipotent across human (pKb 7.7), rat (pKb 7.7), and guinea pig (pKb 7.5) TRPV1. The quaternary salt experiment suggests the binding site is extracellularly accessible. Due to high intrinsic clearance, it is not suitable for in vivo studies but is a useful in vitro tool compound. The compound was discovered via HTS of a urea template, with structure-activity relationships explored around the left-hand aryl, R1 (N-ethyl optimal), and right-hand phenyl substitutions [1].
SB452533 is a research-grade compound that serves as a foundational tool in the study of TRPV1 biology. Its significance lies in its role as a reference standard and structural template for the development of more advanced TRPV1 antagonists, including the clinical candidate SB-705498. It is a valuable chemical probe for exploring the structure-activity relationships (SAR) of urea-based TRPV1 antagonists. This product is for research use only and is not for human or veterinary use. |
| Exact Mass |
375.095
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| CAS # |
459429-39-1
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| PubChem CID |
9842609
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| Appearance |
White to off-white solid powder
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| LogP |
4.682
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
23
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| Complexity |
366
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCN(CCNC(=O)NC1=CC=CC=C1Br)C2=CC=CC(=C2)C
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| InChi Key |
IFJYEGJUQIBBQV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H22BrN3O/c1-3-22(15-8-6-7-14(2)13-15)12-11-20-18(23)21-17-10-5-4-9-16(17)19/h4-10,13H,3,11-12H2,1-2H3,(H2,20,21,23)
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| Chemical Name |
1-(2-bromophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea
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| Synonyms |
SB452533 SB-452533 SB 452533
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~265.75 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.64 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (6.64 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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