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Purity: ≥98%
SRT3190 (SRT-3190) is a potent and selective antagonist of CXCR2 (C-X-C chemokine receptor type 2) and an activator of SIRT1 with anti-Inflammatory and immunomodulatory activity. SRT3190 may find application in the study of diseases mediated by chemokines. Integral membrane proteins known as CXCRs (CXC chemokine receptors) bind and react specifically to cytokines within the CXC chemokine family. Given that they span the cell membrane seven times, they are referred to as seven transmembrane (7-TM) proteins, and they constitute one subfamily of the large family of G protein-linked chemokine receptors. Currently, CXCR1 through CXCR7 are the seven CXC chemokine receptors that are known to exist in mammals. Closely related receptors CXCR1 and CXCR2 are able to identify CXC chemokines with an E-L-R amino acid motif right next to their CXC motif.
| Targets |
CXCR2
C-X-C chemokine receptor type 2 (CXCR2) (Ki = 0.7 nM for human CXCR2; IC₅₀ = 1.3 nM for inhibiting CXCL8 binding to human CXCR2; IC₅₀ = 1.8 nM for inhibiting CXCR2-mediated calcium mobilization); >1000-fold selectivity over CXCR1 (Ki = 320 nM), CXCR3, CXCR4, CCR1, CCR2, CCR5 (Ki > 1000 nM for all) [1] |
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| ln Vitro |
SRT3190 (Reference Example 2) an antagonist of CXCR2, is utilized in the research of chemokine mediated diseases[1].
CXCR2 binding and selective inhibition: SRT3190, a pyrimidyl sulfonamide derivative, exhibited high binding affinity to human CXCR2 with a Ki value of 0.7 nM, and competitively inhibited the binding of CXCL8 (IL-8) to human CXCR2-expressing cells with an IC₅₀ of 1.3 nM. It showed weak affinity for CXCR1 (Ki = 320 nM) and no significant binding to other chemokine receptors (CXCR3, CXCR4, CCR1, CCR2, CCR5) at concentrations up to 10 μM, confirming high CXCR2 selectivity [1] - CXCR2 functional inhibition: In CHO cells stably expressing human CXCR2, SRT3190 dose-dependently suppressed CXCL8-induced calcium mobilization with an IC₅₀ of 1.8 nM. It also inhibited CXCL8-mediated chemotaxis of human peripheral blood neutrophils, reducing migration by 78% at 10 nM and 91% at 100 nM. Additionally, it blocked CXCL1- and CXCL5-induced CXCR2 activation (IC₅₀ = 2.1 nM and 2.4 nM, respectively) without affecting TNF-α-induced immune cell activation [1] - Metabolic stability: In human liver microsome assays, SRT3190 demonstrated good metabolic stability with a half-life (t₁/₂) of 95 minutes and intrinsic clearance (CLint) of 18 μL/min/mg protein [1] |
| ln Vivo |
Mouse carrageenan-induced paw edema model: Oral administration of SRT3190 (3, 10, 30 mg/kg) 1 hour before carrageenan injection dose-dependently reduced paw edema (by 38%, 62%, 76% at 4 hours post-injection) and inflammatory cell infiltration (neutrophil count in paw tissue reduced by 45%, 68%, 80% at 30 mg/kg). It also decreased local tissue levels of pro-inflammatory cytokines (IL-6, TNF-α) by 55% and 60% at 30 mg/kg [1]
- Mouse LPS-induced acute inflammation model: Intraperitoneal administration of SRT3190 (1, 3, 10 mg/kg) 30 minutes before LPS challenge reduced plasma IL-6 and CXCL8 levels by 40–70% (dose-dependent) and decreased lung MPO activity (a marker of neutrophil infiltration) by 35%, 58%, 72% compared to vehicle [1] |
| Enzyme Assay |
CXCR2 radioligand binding assay: Membranes from human CXCR2-expressing HEK293 cells were prepared and suspended in binding buffer (Tris-HCl, MgCl₂, 0.1% BSA). SRT3190 was serially diluted (0.001–1000 nM) and mixed with membranes and tritiated CXCL8. The mixture was incubated at 25°C for 90 minutes, then filtered through glass fiber filters to separate bound and free ligands. Filters were washed with cold binding buffer, and radioactivity was measured by liquid scintillation counting. Ki and IC₅₀ values were calculated via nonlinear regression analysis of displacement curves [1]
- CXCR2-mediated calcium mobilization assay: CXCR2-expressing CHO cells were loaded with a calcium-sensitive fluorescent dye for 30 minutes at 37°C. SRT3190 (0.001–100 nM) was preincubated with cells for 15 minutes, followed by stimulation with CXCL8 (10 nM). Fluorescence intensity (excitation 340/380 nm, emission 510 nm) was measured in real-time using a microplate reader, and IC₅₀ values were derived from dose-response curves of normalized calcium flux [1] - Receptor selectivity assay: Membranes from cells expressing human CXCR1, CXCR3, CXCR4, CCR1, CCR2, or CCR5 were prepared as described. SRT3190 was tested at concentrations up to 10 μM, and binding affinity (Ki) was determined to assess selectivity against non-target chemokine receptors [1] |
| Cell Assay |
Human neutrophil chemotaxis assay: Human peripheral blood neutrophils were isolated by density gradient centrifugation and resuspended in RPMI 1640 medium. SRT3190 (0.1–100 nM) was mixed with neutrophils, which were then added to the upper chamber of a transwell insert (5 μm pore size). CXCL8, CXCL1, or CXCL5 (10 nM each) was added to the lower chamber, and the plate was incubated at 37°C with 5% CO₂ for 2 hours. Migrated neutrophils in the lower chamber were counted using a hemocytometer, and inhibition rates were calculated relative to vehicle-treated controls [1]
- Neutrophil activation assay: Isolated human neutrophils were pretreated with SRT3190 (10 nM) for 15 minutes, then activated with TNF-α (10 ng/mL) for 30 minutes. Expression of the activation marker CD11b was analyzed by flow cytometry, and superoxide anion production was measured by a chemiluminescence assay to confirm no off-target effects on TNF-α signaling [1] |
| Animal Protocol |
Mouse carrageenan-induced paw edema study: Male CD-1 mice (20–25 g, n=6 per group) were administered SRT3190 dissolved in 0.5% methylcellulose via oral gavage at doses of 3, 10, 30 mg/kg 1 hour before intraplantar injection of 1% carrageenan (50 μL) into the right hind paw. Vehicle group received 0.5% methylcellulose. Paw edema volume was measured using a plethysmometer at 1, 2, 4, 6 hours post-carrageenan injection. At 6 hours, mice were euthanized, and paw tissue was collected to count neutrophils and measure cytokine levels by ELISA [1]
- Mouse LPS-induced acute inflammation study: Female C57BL/6 mice (18–22 g, n=7 per group) were administered SRT3190 dissolved in sterile saline via intraperitoneal injection at doses of 1, 3, 10 mg/kg 30 minutes before intraperitoneal LPS challenge (1 mg/kg). Vehicle group received equal volume of saline. Six hours post-LPS challenge, mice were euthanized; blood was collected to measure plasma cytokine levels, and lung tissue was harvested to assay MPO activity [1] - Rat pharmacokinetic study: Male Sprague-Dawley rats (200–250 g, n=5 per time point) were administered SRT3190 via oral gavage (10 mg/kg) or intravenous injection (5 mg/kg). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, 24 hours post-dosing. Plasma drug concentrations were measured by LC-MS/MS, and pharmacokinetic parameters were calculated using non-compartmental analysis [1] |
| ADME/Pharmacokinetics |
In rats: Oral administration (10 mg/kg) resulted in a peak plasma concentration (Cₘₐₓ) of 1.6 μg/mL, a time to reach Cₘₐₓ (Tₘₐₓ) of 1.1 h, a terminal half-life (t₁/₂) of 5.8 h, a volume of distribution (Vd) of 3.2 L/kg, and an oral bioavailability of 52%. The clearance (CL) of intravenous injection (5 mg/kg) was 0.48 L/h/kg [1]
- Tissue distribution: In rats, 2 hours after oral administration (10 mg/kg), SRT3190 was mainly distributed in inflamed tissues and major organs, with tissue/plasma ratios of: liver 2.7, lung 2.4, spleen 2.1, kidney 1.9, and inflamed paw tissue 1.7; the concentration in brain tissue was low (tissue/plasma ratio = 0.3) [1] - In vitro metabolism: In rat liver microsomes, the metabolic half-life of SRT3190 was 102 minutes; the main metabolic pathways included hydroxylation and sulfation, and no toxic metabolites were detected [1] |
| Toxicity/Toxicokinetics |
Plasma protein binding: SRT3190 was 92% bound to human plasma and 90% bound to rat plasma by ultrafiltration [1] - Acute toxicity: The oral LD₅₀ of SRT3190 was > 200 mg/kg in mice and rats. No significant toxicity (weight loss, seizures, respiratory depression, death) was observed at doses up to 100 mg/kg in a 7-day acute study [1] - Subchronic toxicity: SRT3190 did not cause significant changes in body weight, food intake, hematological parameters or liver and kidney function in a 14-day repeated oral administration study in rats (10, 30, 100 mg/kg/day). No histopathological abnormalities were found in major organs (liver, kidneys, heart, lungs, spleen) [1]
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| References | |
| Additional Infomation |
SRT3190 is a potent, highly selective, and orally bioavailable CXCR2 antagonist belonging to the pyrimidine sulfonamide derivative class, disclosed in patent WO2010007427A1 [1]. Its core mechanism of action is competitive binding to human CXCR2, blocking the interaction between pro-inflammatory chemokines (CXCL8, CXCL1, CXCL5) and their receptors, thereby inhibiting downstream signal transduction (calcium mobilization) and the recruitment/activation of neutrophils at inflammatory sites [1]. This compound is intended for the treatment of chemokine-mediated diseases, including inflammatory diseases (such as rheumatoid arthritis, acute lung injury, psoriasis), autoimmune diseases, and other diseases characterized by excessive neutrophil infiltration [1]. SRT3190 exhibits good pharmacokinetic properties, including good oral bioavailability. High bioavailability, moderate tissue distribution, can target inflammatory sites, and a half-life suitable for once-daily administration [1] - High selectivity for CXCR2 can minimize off-target effects on other chemokine receptors, thereby reducing the risk of unintended immunomodulatory or systemic side effects [1]
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| Molecular Formula |
C18H23F2N5O4S2
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| Molecular Weight |
475.53
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| Exact Mass |
475.116
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| Elemental Analysis |
C, 45.46; H, 4.88; F, 7.99; N, 14.73; O, 13.46; S, 13.48
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| CAS # |
1204707-73-2
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| Related CAS # |
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| PubChem CID |
59149652
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| Appearance |
White to off-white solid powder
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| LogP |
2.727
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
31
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| Complexity |
670
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| Defined Atom Stereocenter Count |
2
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| SMILES |
OC[C@@H]([C@@H](NC1=CC(NS(N2CCC2)(=O)=O)=NC(SCC3=C(C(F)=CC=C3)F)=N1)C)O
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| InChi Key |
QVKPEMXUBULFBM-FZMZJTMJSA-N
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| InChi Code |
InChI=1S/C18H23F2N5O4S2/c1-11(14(27)9-26)21-15-8-16(24-31(28,29)25-6-3-7-25)23-18(22-15)30-10-12-4-2-5-13(19)17(12)20/h2,4-5,8,11,14,26-27H,3,6-7,9-10H2,1H3,(H2,21,22,23,24)/t11-,14-/m0/s1
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| Chemical Name |
N-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2S,3R)-3,4-dihydroxybutan-2-yl]amino]pyrimidin-4-yl]azetidine-1-sulfonamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.26 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 (5.26 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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 (5.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1029 mL | 10.5146 mL | 21.0292 mL | |
| 5 mM | 0.4206 mL | 2.1029 mL | 4.2058 mL | |
| 10 mM | 0.2103 mL | 1.0515 mL | 2.1029 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
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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