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| 5mg |
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CCR2 antagonist 4 (Teijin compound 1) is a novel and potent CCR2 antagonist (IC50 = 180 nM for CCR2b) with anti-inflammatory and immunomodulatory effects.
| Targets |
Teijin compound 1 targets chemokine receptor 2b (CCR2b) (Ki = 0.4 nM, competitive binding mode) [1]
Teijin compound 1 targets chemokine receptor 5 (CCR5) (Ki = 3.2 nM, competitive binding mode) [2] |
|---|---|
| ln Vitro |
Teijin compound 1 binding in CCR2 is largely facilitated by Ile263 and Thr292 in CCR2. A highly conserved residue found in several CC chemokine receptors, Glu291 in TM7 plays a major role in the binding of protonated CCR2 antagonist 4 and CCL2. CCR2 antagonist 4 also interacts strongly with His121 on TM3 and Ile263 on TM6 [2]. Vp-TSL specifically targets the aortic plaque endothelium VCAM-1 and CCR2 antagonist 4 in ApoE-deficient animals, thereby inhibiting the adherence and infiltration of mouse monocyte/macrophage line (RAW 264.7) into the aorta [3].
- CCR2b receptor binding and functional antagonism: Teijin compound 1 potently bound to human CCR2b with Ki = 0.4 nM, competing with the natural ligand MCP-1 (CCL2) for receptor binding. It dose-dependently inhibited MCP-1-induced calcium mobilization in CCR2b-transfected CHO cells, with IC50 = 1.2 nM. At 10 nM, it blocked MCP-1-mediated cell migration by 85% in transwell assays [1] - CCR5 receptor antagonistic activity: The compound also bound to human CCR5 with Ki = 3.2 nM, inhibiting RANTES (CCL5)-induced calcium flux in CCR5-transfected HEK293 cells (IC50 = 4.5 nM). It showed selectivity over other chemokine receptors (CCR1, CCR3, CXCR4; Ki > 100 nM) [2] - Inhibition of monocyte adhesion and transmigration: Teijin compound 1 (1 nM, 10 nM, 100 nM) suppressed adhesion of human peripheral blood monocytes to TNF-α-activated human umbilical vein endothelial cells (HUVECs). At 10 nM, adhesion was reduced by 65% compared to control. It also inhibited monocyte transmigration through activated HUVEC monolayers, with a 70% inhibition rate at 10 nM [3] |
| Enzyme Assay |
- CCR2b receptor binding assay: CCR2b-transfected CHO cells were incubated with a radioactive-labeled MCP-1 analog and Teijin compound 1 at gradient concentrations (0.01-100 nM) in binding buffer (pH 7.4) for 1 hour at 4°C. Unbound ligand was removed by washing, and cell-associated radioactivity was measured. Ki values were calculated using competitive binding equations [1]
- CCR5 receptor binding assay: CCR5-transfected HEK293 cells were incubated with radioactive-labeled RANTES and Teijin compound 1 (0.1-100 nM) for 1 hour at 4°C. After washing, bound radioactivity was detected, and Ki was determined by competitive displacement analysis [2] - Calcium mobilization assay: CCR2b-transfected CHO cells or CCR5-transfected HEK293 cells were loaded with a calcium-sensitive fluorescent dye for 30 minutes at 37°C. Cells were pre-treated with Teijin compound 1 (0.01-100 nM) for 15 minutes, then stimulated with MCP-1 (100 nM) or RANTES (100 nM). Fluorescence intensity changes were recorded in real-time to calculate IC50 for inhibiting calcium flux [1][2] |
| Cell Assay |
- Monocyte adhesion assay: Human peripheral blood monocytes were isolated and labeled with a fluorescent dye. TNF-α-activated HUVECs grown in 96-well plates were pre-treated with Teijin compound 1 (1-100 nM) for 30 minutes. Labeled monocytes were added and incubated for 1 hour at 37°C. Non-adherent cells were washed away, and fluorescence intensity of adherent cells was measured to calculate adhesion inhibition rate [3]
- Monocyte transmigration assay: Transwell chambers with porous membranes were coated with TNF-α-activated HUVEC monolayers. Teijin compound 1 (1-100 nM) was added to both upper and lower chambers. Fluorescently labeled monocytes were seeded into the upper chamber, and MCP-1 (100 nM) was added to the lower chamber as a chemoattractant. After 4 hours of incubation, migrated monocytes in the lower chamber were quantified by fluorescence measurement [3] - CCR2b-mediated cell migration assay: CCR2b-transfected CHO cells were pre-treated with Teijin compound 1 (0.1-100 nM) for 15 minutes, then seeded into the upper chamber of Transwell plates. MCP-1 (100 nM) was added to the lower chamber, and cells were incubated for 24 hours. Migrated cells on the lower membrane surface were fixed, stained, and counted to determine migration inhibition [1] |
| References |
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| Additional Infomation |
Chemical Classification: Teijin Compound 1 is a small molecule dual antagonist of CCR2b and CCR5, belonging to the (R)-3-aminopyrrolidine class of compounds [1] - Mechanism of Action: This compound competitively binds to the ligand-binding pockets of CCR2b and CCR5, preventing the binding of their natural ligands (MCP-1 for CCR2b and RANTES for CCR5). This blocks downstream signaling pathways (e.g., calcium mobilization, PI3K/Akt activation), thereby inhibiting chemokine-mediated monocyte recruitment, adhesion, and transendothelial migration [1][2][3] - Target Background: CCR2b and CCR5 are G protein-coupled chemokine receptors expressed on monocytes, macrophages, and T cells. Chemokines (such as MCP-1 and RANTES) activate these cells, promoting the recruitment of immune cells to sites of inflammation, thereby participating in the pathogenesis of chronic inflammatory diseases and atherosclerosis [1][3]. Therapeutic potential: Teijin compound 1 is a potent and selective dual CCR2b/CCR5 antagonist that shows promise in inhibiting monocyte-mediated inflammation. It is expected to be used to treat inflammatory diseases such as rheumatoid arthritis, atherosclerosis and inflammatory bowel disease [1][3].
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| Molecular Formula |
C21H22CL2F3N3O2
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|---|---|
| Molecular Weight |
476.3195
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| Exact Mass |
439.127
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| CAS # |
226226-39-7
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| Related CAS # |
CCR2 antagonist 4 hydrochloride;1313730-14-1
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| PubChem CID |
44453327
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| Appearance |
White to off-white solid powder
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| LogP |
5.634
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
597
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CN(C[C@@H]1NC(=O)CNC(=O)C2=CC(=CC=C2)C(F)(F)F)CC3=CC=C(C=C3)Cl
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| InChi Key |
BAOQJSULMWXFRK-GOSISDBHSA-N
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| InChi Code |
InChI=1S/C21H21ClF3N3O2/c22-17-6-4-14(5-7-17)12-28-9-8-18(13-28)27-19(29)11-26-20(30)15-2-1-3-16(10-15)21(23,24)25/h1-7,10,18H,8-9,11-13H2,(H,26,30)(H,27,29)/t18-/m1/s1
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| Chemical Name |
N-[2-[[(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide
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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 |
| 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 : ≥ 50 mg/mL (~113.67 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.68 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 (5.68 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 (5.68 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 | 2.0994 mL | 10.4971 mL | 20.9943 mL | |
| 5 mM | 0.4199 mL | 2.0994 mL | 4.1989 mL | |
| 10 mM | 0.2099 mL | 1.0497 mL | 2.0994 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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