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Purity: ≥98%
RS-102895 HCl (RS 102895), the hydrochloride salt of RS102895, is a novel and potent chemokine receptor CCR2 antagonist anticancer activity. It exhibits no effect on CCR1 but inhibits CCR2 with an IC50 of 360 nM. At IC50 values of 32 nM and 1.7 μM, respectively, RS-102895 HCl inhibits MCP-1-stimulated calcium influx and chemotaxis. Moreover, it blocks 5-HT1A, α1A, and α1D receptors.
| Targets |
CCR2 ( IC50 = 360 nM ); CCR1 ( IC50 = 17800 nM ); Human α1a receptor ( IC50 = 130 nM ); Human α1d receptor ( IC50 = 320 nM ); 5HT-1a receptor ( IC50 = 470 nM )
RS-102895 is a potent and selective antagonist of chemokine (C-C motif) receptor 2 (CCR2), which is the receptor for CCL2. The compound belongs to a class of compounds called spiropiperidines. [1] |
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| ln Vitro |
RS-102895's effect on leukocyte chemotaxis toward CCL2 is validated by an in vitro chemotaxis assay. Based on the data, it appears that elevated CCL2 in SS kidneys plays a significant role in the initial leukocyte recruitment. Blocking this recruitment with RS-102895 then reduces hypertension and renal damage.[2]
In an in vitro chemotaxis assay using peritoneal macrophages isolated from Dahl salt-sensitive rats, pre-incubation with RS-102895 effectively reduced macrophage migration towards a chemokine CCL2 gradient. The compound reduced migration at a low concentration (1 µM) and completely blocked chemotaxis to baseline levels at a concentration of 350 µM. [1] Furthermore, incubation of naive macrophages with urine collected from rats chronically treated in vivo with RS-102895 (5 mg/kg/day for 21 days) significantly blunted chemotaxis towards CCL2 compared to incubation with urine from vehicle-treated rats, validating that a biologically active level of the drug was achieved in vivo. [1] |
| ln Vivo |
The biological function of the CCL2/CCR2 pathway is tested by daily administration of CCR2 antagonist RS-102895. Assessments are made of blood pressure, renal damage, and renal leukocyte infiltration. The findings show that following a 21-day high-salt diet, RS-102895 treatment reduces hypertension and renal damage. It is found that by day three of the high-salt diet, renal leukocyte infiltration is blunted. [2]
Daily administration of RS-102895 (5 mg/kg/day, i.p.) to Dahl salt-sensitive rats concurrently with a high-salt (4% NaCl) diet significantly attenuated the development of salt-sensitive hypertension. After 21 days on the high-salt diet, the mean arterial pressure (MAP) in the RS-102895-treated group was 144.3 ± 2.2 mmHg, compared to 158.9 ± 4.8 mmHg in the vehicle-treated group. [1] RS-102895 treatment also significantly ameliorated renal damage. Urinary albumin excretion at day 21 of the high-salt diet was 43.4 ± 5.1 mg/day in the treated group versus 114.7 ± 15.2 mg/day in the vehicle group. Similarly, urinary protein excretion was reduced to 96.8 ± 11.6 mg/day compared to 231.6 ± 24.5 mg/day in controls. [1] Histological assessment of the kidneys after 21 days showed a significant reduction in the glomerular damage index and a trend towards decreased tubular cast area in the outer medulla in the RS-102895-treated group compared to the vehicle group. [1] RS-102895 prevented early renal leukocyte infiltration. After only 3 days of a high-salt diet, the total number of CD45+ leukocytes infiltrating the kidney was significantly lower in the RS-102895-treated group (1.4 ± 0.1 x 10⁶ cells/kidney) compared to the vehicle group (1.9 ± 0.2 x 10⁶ cells/kidney). This reduction included T cells (both helper and cytotoxic subsets) and B cells. However, this significant difference in leukocyte infiltration was not observed after 21 days of high-salt diet. [1] The compound did not affect the number of circulating leukocytes at either 3 or 21 days of treatment, nor did it alter M1/M2 macrophage polarization in the kidney at day 21. [1] |
| Cell Assay |
After being collected, peritoneal cells are centrifuged, filtered through a 40-μm strainer, and then resuspended in medium without serum. After using a hemocytometer to count the cells, the concentration was adjusted to 107 cells/mL. The cells are left untreated or incubated for 30 minutes with DMSO vehicle, urine from animals treated with CCR2 antagonists in vivo, or RS-102895 at different concentrations.
A chemotaxis assay was performed to assess the effect of RS-102895 on leukocyte migration. Peritoneal macrophages were isolated from Dahl salt-sensitive rats maintained on a low-salt diet. Cells were either left untreated or pre-incubated for 30 minutes with varying concentrations of RS-102895> dissolved in DMSO, with DMSO vehicle alone, or with urine collected from in vivo treated rats. The assay was conducted using a 24-well plate format with cell culture inserts containing 3-µm pores. Serum-free medium (RPMI-1640 with 1% fatty acid-free BSA), with or without CCL2 (1000 ng/mL), was added to the bottom wells. After wetting the inserts, 10⁶ cells were loaded into the top chamber. The plate was incubated at 37°C with 5% CO₂ for 4 hours. Chemotaxis was quantified by counting the number of cells that migrated to the bottom well. The chemotaxis index was calculated as the number of migrated cells in the experimental condition divided by the number migrated in the no-CCL2 control. [1] |
| Animal Protocol |
Seven-week-old male Dahl salt-sensitive rats were surgically implanted with radiotelemetry transmitters in the right carotid artery for continuous blood pressure monitoring. After a 7-day recovery period and 7 days of baseline recording, rats were randomly divided into treatment groups. Starting at 9 weeks of age, rats were switched from a low-salt (0.4% NaCl) diet to a high-salt (4% NaCl) diet and received daily intraperitoneal (i.p.) injections for either 3 or 21 days. [1]
The treatment group received RS-102895 at a dose of 5 mg/kg/day. The compound was dissolved in dimethyl sulfoxide (DMSO). The control group received an equal volume of DMSO vehicle. Injections were administered daily throughout the high-salt diet period. [1] Body mass, urinary sodium excretion (as an index of sodium intake), and renal function parameters were monitored periodically. At the end of the 3- or 21-day treatment period, animals were deeply anesthetized, kidneys were flushed and extracted for leukocyte isolation and histology, and blood and urine were collected for analysis. [1] |
| References | |
| Additional Infomation |
RS-102895 was used as a pharmacological tool to block the CCL2/CCR2 signaling axis in vivo and in vitro in the context of salt-sensitive hypertension. [1]
The study proposes a timeline where RS-102895 initially blunts renal leukocyte infiltration (observed at day 3 of high salt), which subsequently leads to reduced renal damage (observed from day 7 onwards) and an attenuated hypertensive response (observed from day 8 onwards). [1] The findings suggest that the CCL2/CCR2 pathway plays a crucial role in the early recruitment of leukocytes to the kidney during salt-sensitive hypertension, and blocking this pathway can ameliorate disease progression. [1] |
| Molecular Formula |
C21H22CLF3N2O2
|
|---|---|
| Molecular Weight |
426.8598
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| Exact Mass |
426.13
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| Elemental Analysis |
C, 59.09; H, 5.20; Cl, 8.30; F, 13.35; N, 6.56; O, 7.50
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| CAS # |
1173022-16-6
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| Related CAS # |
RS102895; 300815-41-2
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| PubChem CID |
16759153
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| Appearance |
White to off-white solid powder
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| LogP |
4.188
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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 |
3
|
| Heavy Atom Count |
29
|
| Complexity |
552
|
| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl[H].FC(C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C2(C3=C([H])C([H])=C([H])C([H])=C3N([H])C(=O)O2)C([H])([H])C1([H])[H])(F)F
|
| InChi Key |
KRRISOFSWVKYBF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H21F3N2O2.ClH/c22-21(23,24)16-7-5-15(6-8-16)9-12-26-13-10-20(11-14-26)17-3-1-2-4-18(17)25-19(27)28-20;/h1-8H,9-14H2,(H,25,27);1H
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| Chemical Name |
1'-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1H-3,1-benzoxazine-4,4'-piperidine]-2-one;hydrochloride
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| Synonyms |
RS-102895HCl; RS-102895; RS 102895; RS-102895 HCl; RS102895
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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: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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: 41.7~85 mg/mL (97.6~199.1 mM)
Ethanol: 85 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.87 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 20.8 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: ≥ 2.08 mg/mL (4.87 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 20.8 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: ≥ 2.08 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 5%DMSO+ Corn oil: 4.5mg/ml (10.54mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3427 mL | 11.7134 mL | 23.4269 mL | |
| 5 mM | 0.4685 mL | 2.3427 mL | 4.6854 mL | |
| 10 mM | 0.2343 mL | 1.1713 mL | 2.3427 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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