| Size | Price | Stock | Qty |
|---|---|---|---|
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg | |||
| Other Sizes |
Purity: ≥98%
SRT3109 (SRT-3109) is a novel and potent antagonist of CXCR2 (C-X-C chemokine receptor type 2) with potential anti-Inflammatory and immunomodulatory activity. It is used in the study of chemokine-mediated diseases and inhibits CXCR2 with a pIC50 of 8.2. Integral membrane proteins called CXCRs, or CXC chemokine receptors, are selectively bind to and react to members of the CXC chemokine family of cytokines. Seven transmembrane (7-TM) proteins, so named because they span the cell membrane seven times, are a large family of G protein-linked receptors that comprise one subfamily of chemokine receptors. CXCR1 through CXCR7 are the seven CXC chemokine receptors that are currently recognized in mammals. The CXC motif of CXC chemokines that have an E-L-R amino acid motif right next to it are recognized by the closely related receptors CXCR1 and CXCR2.
| Targets |
CXCR2 ( pIC50 = 8.2 )
C-X-C chemokine receptor type 2 (CXCR2) (Ki = 0.9 nM for human CXCR2; IC₅₀ = 1.5 nM for inhibiting CXCL8 (IL-8) binding to human CXCR2; IC₅₀ = 2.1 nM for inhibiting CXCR2-mediated calcium mobilization); >1000-fold selectivity over CXCR1 (Ki = 350 nM), CXCR3, CXCR4, CCR1, CCR2, CCR5, CCR7 (Ki > 1000 nM for all) [1] |
|---|---|
| ln Vitro |
SRT3109 (Example 1) is a CXCR2 antagonist that is used in the study of chemokine-mediated diseases. It has a pIC50 of 8.2.[1]
CXCR2 binding affinity and selectivity: SRT3109, a pyrimidyl sulfonamide derivative, binds specifically to human CXCR2 with high affinity (Ki = 0.9 nM) as determined by radioligand displacement assay. It competitively inhibits the interaction between CXCL8 and human CXCR2-expressing cells, with an IC₅₀ of 1.5 nM. The compound shows weak cross-reactivity with CXCR1 (Ki = 350 nM) and no significant binding to other chemokine receptors (CXCR3, CXCR4, CCR1, CCR2, CCR5, CCR7) at concentrations up to 10 μM, confirming high CXCR2 selectivity [1] - CXCR2 functional inhibition: In CHO cells stably transfected with human CXCR2, SRT3109 dose-dependently suppresses CXCL8-induced calcium flux, with an IC₅₀ of 2.1 nM. It effectively inhibits CXCL8-mediated chemotaxis of human peripheral blood neutrophils, reducing migration by 75% at 10 nM and 89% at 100 nM. Additionally, it blocks CXCL1- and CXCL5-induced CXCR2 activation (IC₅₀ = 2.3 nM and 2.6 nM, respectively) without affecting TNF-α-induced CD11b expression or superoxide anion production in neutrophils [1] - Metabolic stability: SRT3109 exhibits good metabolic stability in human liver microsomes, with a half-life (t₁/₂) of 88 minutes and intrinsic clearance (CLint) of 20 μL/min/mg protein. In rat liver microsomes, it has a metabolic half-life of 95 minutes, with hydroxylation and glucuronidation identified as major metabolic pathways [1] |
| ln Vivo |
Mouse carrageenan-induced paw edema model: Oral administration of SRT3109 (3, 10, 30 mg/kg) 1 hour prior to carrageenan injection results in dose-dependent reduction of paw edema. At 4 hours post-carrageenan challenge, edema volume is reduced by 35%, 58%, and 73% compared to vehicle. The compound also decreases neutrophil infiltration in paw tissue (42%, 65%, 78% reduction at 3, 10, 30 mg/kg) and lowers local levels of pro-inflammatory cytokines IL-6 and TNF-α by 52% and 57% at 30 mg/kg [1]
- Mouse LPS-induced acute inflammation model: Intraperitoneal injection of SRT3109 (1, 3, 10 mg/kg) 30 minutes before LPS challenge dose-dependently reduces plasma IL-6 and CXCL8 levels (38–68% reduction) and inhibits lung myeloperoxidase (MPO) activity (a marker of neutrophil infiltration) by 32%, 55%, and 70% compared to vehicle [1] |
| Enzyme Assay |
CXCR2 radioligand binding assay: Membranes prepared from human CXCR2-expressing HEK293 cells are suspended in binding buffer containing Tris-HCl, MgCl₂, and 0.1% BSA. SRT3109 is serially diluted (0.001–1000 nM) and mixed with the membrane suspension and tritiated CXCL8. The mixture is incubated at 25°C for 90 minutes, then filtered through glass fiber filters to separate bound and free ligands. Filters are washed with cold binding buffer, and radioactivity is quantified by liquid scintillation counting. Ki and IC₅₀ values are calculated using nonlinear regression analysis of displacement curves [1]
- CXCR2-mediated calcium mobilization assay: CXCR2-expressing CHO cells are loaded with a calcium-sensitive fluorescent dye for 30 minutes at 37°C. SRT3109 (0.001–100 nM) is preincubated with the cells for 15 minutes, followed by stimulation with 10 nM CXCL8. Fluorescence intensity (excitation at 340/380 nm, emission at 510 nm) is measured in real-time using a microplate reader. IC₅₀ values are derived from dose-response curves of normalized calcium flux [1] - Chemokine receptor selectivity assay: Membranes from cells expressing human CXCR1, CXCR3, CXCR4, CCR1, CCR2, CCR5, or CCR7 are prepared as described for CXCR2. SRT3109 is tested at concentrations up to 10 μM, and binding affinity (Ki) is determined via radioligand displacement assay to evaluate selectivity against non-target receptors [1] |
| Cell Assay |
Human neutrophil chemotaxis assay: Human peripheral blood neutrophils are isolated by density gradient centrifugation and resuspended in RPMI 1640 medium. SRT3109 (0.1–100 nM) is mixed with the neutrophils, which are then added to the upper chamber of a Transwell insert (5 μm pore size). The lower chamber is filled with RPMI 1640 medium containing 10 nM CXCL8, CXCL1, or CXCL5. The plate is incubated at 37°C with 5% CO₂ for 2 hours. Migrated neutrophils in the lower chamber are counted using a hemocytometer, and inhibition rates are calculated relative to vehicle-treated controls [1]
- Neutrophil activation assay: Isolated human neutrophils are pretreated with SRT3109 (10 nM) for 15 minutes, then activated with 10 ng/mL TNF-α for 30 minutes. Expression of the neutrophil activation marker CD11b is analyzed by flow cytometry. Superoxide anion production is measured using a chemiluminescence assay to confirm that SRT3109 does not interfere with TNF-α-mediated signaling [1] |
| Animal Protocol |
Mouse carrageenan-induced paw edema study: Male CD-1 mice (20–25 g, n=6 per group) are administered SRT3109 dissolved in 0.5% methylcellulose via oral gavage at doses of 3, 10, or 30 mg/kg. Dosing occurs 1 hour before intraplantar injection of 50 μL 1% carrageenan into the right hind paw. Vehicle-treated mice receive 0.5% methylcellulose alone. Paw edema volume is measured using a plethysmometer at 1, 2, 4, and 6 hours post-carrageenan injection. At 6 hours, mice are euthanized, and paw tissue is collected to count neutrophils and measure IL-6/TNF-α levels via ELISA [1]
- Mouse LPS-induced acute inflammation study: Female C57BL/6 mice (18–22 g, n=7 per group) are injected intraperitoneally with SRT3109 dissolved in sterile saline at doses of 1, 3, or 10 mg/kg. Dosing occurs 30 minutes before intraperitoneal challenge with 1 mg/kg LPS. Vehicle-treated mice receive sterile saline alone. Six hours post-LPS challenge, mice are euthanized; blood is collected to measure plasma IL-6/CXCL8 levels via ELISA, and lung tissue is harvested to assay MPO activity [1] - Rat pharmacokinetic study: Male Sprague-Dawley rats (200–250 g, n=5 per time point) are administered SRT3109 via oral gavage (10 mg/kg) or intravenous injection (5 mg/kg). Blood samples are collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dosing. Plasma is separated, and drug concentrations are measured by LC-MS/MS. Pharmacokinetic parameters are calculated using non-compartmental analysis [1] |
| ADME/Pharmacokinetics |
In rats (oral, 10 mg/kg): peak plasma concentration (Cₘₐₓ) = 1.4 μg/mL; time to peak concentration (Tₘₐₓ) = 1.2 h; terminal half-life (t₁/₂) = 5.5 h; volume of distribution (Vd) = 3.4 L/kg; oral bioavailability = 49% [1]
- In rats (intravenous, 5 mg/kg): clearance (CL) = 0.51 L/h/kg [1] - Tissue distribution (rat, 2 h after oral administration, 10 mg/kg): preferentially distributed in inflamed paw tissue (tissue/plasma ratio = 1.6) and major organs, including liver (2.5), lung (2.2), spleen (2.0) and kidney (1.8); low brain permeability (tissue/plasma ratio = 0.4) [1] - In vitro metabolism: The main metabolic pathways in rat liver microsomes included hydroxylation and glucuronidation; no toxic metabolites were detected. The metabolic half-life in rat liver microsomes was 95 minutes [1] |
| Toxicity/Toxicokinetics |
Plasma protein binding rate: 91% in human plasma and 89% in rat plasma (measured by ultrafiltration) [1] - Acute toxicity: oral LD₅₀ > 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 study [1] - Subchronic toxicity (repeated oral administration in rats for 14 days, 10–100 mg/kg/day): no significant changes were observed in body weight, food intake, hematological parameters (erythrocytes, white blood cells, platelets) or liver and kidney function (ALT, AST, creatinine, BUN). No histopathological abnormalities were detected in major organs (liver, kidneys, heart, lungs, spleen) [1]
|
| References | |
| Additional Infomation |
SRT3109 is a potent, highly selective, and orally bioavailable CXCR2 antagonist belonging to the pyrimidine sulfonamide derivative class. It has been disclosed in international patent WO2010007427A1 [1]. - Mechanism of action: It competitively binds 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 the site of inflammation [1]. - Intended therapeutic applications: Chemokine-mediated diseases, including inflammatory diseases (e.g., rheumatoid arthritis, acute lung injury, psoriasis), autoimmune diseases, and other diseases characterized by excessive neutrophil infiltration [1]. - Pharmacological advantages: Good oral bioavailability, tissue distribution targeting the site of inflammation, and a half-life supporting once-daily administration; high selectivity for CXCR2 minimizes off-target effects on other chemokine receptors, thereby reducing the risk of unintended immunomodulation [1].
|
| Molecular Formula |
C18H23F2N5O4S2
|
|
|---|---|---|
| Molecular Weight |
475.53
|
|
| Exact Mass |
475.115
|
|
| Elemental Analysis |
C, 45.46; H, 4.88; F, 7.99; N, 14.73; O, 13.46; S, 13.48
|
|
| CAS # |
1204707-71-0
|
|
| Related CAS # |
|
|
| PubChem CID |
44602493
|
|
| Appearance |
White to off-white solid powder
|
|
| Density |
1.6±0.1 g/cm3
|
|
| Boiling Point |
726.6±70.0 °C at 760 mmHg
|
|
| Flash Point |
393.3±35.7 °C
|
|
| Vapour Pressure |
0.0±2.5 mmHg at 25°C
|
|
| Index of Refraction |
1.661
|
|
| LogP |
2.07
|
|
| Hydrogen Bond Donor Count |
4
|
|
| Hydrogen Bond Acceptor Count |
12
|
|
| Rotatable Bond Count |
10
|
|
| Heavy Atom Count |
31
|
|
| Complexity |
670
|
|
| Defined Atom Stereocenter Count |
2
|
|
| SMILES |
FC1=C(F)C=CC=C1CSC2=NC(NS(=O)(N3CCC3)=O)=CC(N[C@@H]([C@@H](O)CO)C)=N2
|
|
| InChi Key |
QVKPEMXUBULFBM-RISCZKNCSA-N
|
|
| 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+/m1/s1
|
|
| Chemical Name |
N-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2R,3R)-3,4-dihydroxybutan-2-yl]amino]pyrimidin-4-yl]azetidine-1-sulfonamide
|
|
| Synonyms |
|
|
| HS Tariff Code |
2934.99.9001
|
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (5.78 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 27.5 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: ≥ 2.75 mg/mL (5.78 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 27.5 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: ≥ 2.75 mg/mL (5.78 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA