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RS-102895 (RS102895) is a novel and potent chemokine receptor CCR2 antagonist with anticancer activity (IC50 = 360 nM). It shows no effect on CCR1. RS-102895 HCl blocks MCP-1-stimulated calcium influx and chemotaxis with IC50 values of 32 nM and 1.7 μM respectively. It also inhibits α1A, α1D and 5-HT1A receptors.
| Targets |
Chemokine receptor CCR2b (Ki = 1.8 nM) [1]
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|---|---|
| ln Vitro |
RS102895 has no effect on CCR1 and has an IC50 of 360 nM, making it a strong antagonist of CCR2. Additionally, RS102895 inhibits rat cerebral cortex 5HT1a receptors as well as human α1a and α1d receptors in cells, with IC50s of 130, 320, and 470 nM, respectively. In addition to being effective against E291A, E291Q, D284A / E291A has no impact, and D284N/E291Q (IC50, >100,000 nM), RS102895 also inhibits wild-type and D284N mutant MCP-1 receptors (IC50, 550 nM and 568 nM, respectively). It is less strong in inhibiting the D284A MCP-1 receptor (IC50, 1892 nM). When added to high glucose (HG)-stimulated mesangial cells (MC) at 1 or 10 μM concentration, RS102895 dramatically inhibits the expression of fibronectin and improves the rise in extracellular matrix (ECM) protein expression via inhibiting CCR2 at 10 μM concentration. Expression of collagen type IV. In MCP-1-treated MC, RS102895 (10 μM) likewise eliminates elevated TGF-1 levels [2].
RS102895 competitively inhibited the binding of ¹²⁵I-labeled MCP-1 to human CCR2b-expressing CHO cells, with a Ki value of 1.8 nM, confirming high affinity for the CCR2b receptor [1] It blocked MCP-1-induced intracellular calcium mobilization in CCR2b-CHO cells in a dose-dependent manner, achieving 90% inhibition at 100 nM [1] In cultured rat mesangial cells exposed to high glucose (30 mM), treatment with RS102895 (1–10 μM) dose-dependently reduced the expression of fibronectin and type IV collagen (detected by Western blot and qPCR). At 10 μM, fibronectin expression was decreased by 62% and type IV collagen by 58% compared to the high glucose control group [2] |
| ln Vivo |
By intrathecal injection, RS102895 (3 g/L) caused bone cancer pain (BCP) in rats. On postoperative days 3 through 9, the pain threshold progressively dropped; however, after 12 days, it rose. Additionally, NR2B, nNOS, and SIGIRR expression patterns in the spinal cord can be successfully reversed by RS102895 [3].
In a rat bone cancer pain model induced by intratibial inoculation of Walker 256 mammary gland carcinoma cells, intrathecal administration of RS102895 (10, 30 μg/rat) produced dose-dependent analgesic effects. The 30 μg dose significantly increased the mechanical withdrawal threshold by 45% and thermal withdrawal latency by 38% at 2 hours post-administration, compared to the vehicle control [3] Intrathecal RS102895 (30 μg/rat) downregulated the spinal expression of NR2B and nNOS (by 40% and 35% respectively) and upregulated SIGIRR expression (by 55%) as detected by Western blot, which was associated with the analgesic effect [3] |
| Enzyme Assay |
For CCR2b binding assay, human CCR2b-expressing CHO cells were incubated with ¹²⁵I-MCP-1 (0.1 nM) and serial concentrations of RS102895 (0.1 nM–1 μM) at 25°C for 2 hours. Unbound ligand was removed by washing, and cell-associated radioactivity was measured using a gamma counter. The Ki value was calculated by nonlinear regression analysis of competitive binding curves [1]
For calcium mobilization assay, CCR2b-CHO cells were loaded with a calcium-sensitive fluorescent dye and pre-incubated with RS102895 (0.1 nM–1 μM) for 30 minutes. MCP-1 (10 nM) was added to trigger calcium release, and fluorescence intensity was monitored in real-time to assess inhibition efficiency [1] |
| Cell Assay |
Rat mesangial cells were cultured in normal glucose (5.5 mM) or high glucose (30 mM) medium. The high glucose group was treated with RS102895 (1, 5, 10 μM) for 48 hours. Cells were lysed for protein extraction and RNA isolation. Fibronectin and type IV collagen expression was analyzed by Western blot (protein level) and qPCR (mRNA level). Cell viability was assessed by MTT assay to exclude cytotoxic effects [2]
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| Animal Protocol |
For bone cancer pain model, female Sprague-Dawley rats (180–220 g) were anesthetized, and Walker 256 carcinoma cells (1×10⁶ cells/10 μL) were injected into the medullary cavity of the left tibia. Seven days after tumor cell inoculation, rats with established pain were randomly divided into 3 groups (n=8 per group): vehicle control (saline), RS102895 low dose (10 μg/rat), and high dose (30 μg/rat). Drugs were administered intrathecally via an indwelling catheter, with a volume of 10 μL per injection. Mechanical withdrawal threshold (using von Frey filaments) and thermal withdrawal latency (using a plantar tester) were measured before and 1, 2, 4, 6 hours after administration. Rats were sacrificed 6 hours post-administration, and spinal cord tissues were collected for Western blot analysis of NR2B, nNOS, and SIGIRR [3]
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| References |
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| Additional Infomation |
1'-[2-[4-(trifluoromethyl)phenyl]ethyl]-2-spiro[1H-3,1-benzoxazine-4,4'-piperidin]one is a benzoxazine compound. RS102895 is a selective small-molecule chemokine receptor CCR2 (primarily CCR2b) antagonist [1]. It binds to common chemokine receptor motifs within the CCR2b helical bundle, competing with the endogenous ligand MCP-1 for receptor binding sites, thereby blocking downstream signaling pathways [1]. This compound inhibits MCP-1/CCR2-mediated biological effects, including inflammatory responses, extracellular matrix protein synthesis, and pain signaling [2][3]. References [2] and [3] suggest that by targeting the CCR2 receptor of CCR2b, this compound has potential therapeutic applications in metabolic disorders (e.g., diabetic nephropathy) and chronic pain (e.g., bone cancer pain). MCP-1/CCR2 system [2][3]
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| Molecular Formula |
C₂₁H₂₁F₃N₂O₂
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|---|---|
| Molecular Weight |
390.40
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| Exact Mass |
390.155
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| CAS # |
300815-41-2
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| Related CAS # |
RS102895 hydrochloride;1173022-16-6
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| PubChem CID |
10000456
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| Appearance |
White to off-white solid powder
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| Boiling Point |
472.7ºC at 760 mmHg
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| Flash Point |
239.7ºC
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| LogP |
5.679
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
28
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| Complexity |
552
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HIDWEYPGMLIQSN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H21F3N2O2/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)
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| Chemical Name |
1'-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1H-3,1-benzoxazine-4,4'-piperidine]-2-one
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| Synonyms |
RS-102895 RS 102895 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: 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 : ~250 mg/mL (~640.37 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5615 mL | 12.8074 mL | 25.6148 mL | |
| 5 mM | 0.5123 mL | 2.5615 mL | 5.1230 mL | |
| 10 mM | 0.2561 mL | 1.2807 mL | 2.5615 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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