| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
Matrix metalloproteinase-12 (MMP-12) (Ki=0.2 nM); RXP470.1 is a potent and selective synthetic inhibitor of matrix metalloproteinase-12 (MMP-12). It exhibits >10-fold selectivity for MMP-12 over other MMPs (exact IC50/Ki values not provided in the study).
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| ln Vitro |
- RXP470.1 selectively inhibits murine MMP-12 activity in enzymatic assays, though specific IC50 values were not reported.
- It attenuates monocyte/macrophage invasion in vitro, likely by reducing MMP-12-mediated extracellular matrix degradation. - MMP-12 inhibition: RXP470.1 is a selective MMP-12 inhibitor with a Ki of 0.2 nM against human MMP-12, showing 2-4 orders of magnitude lower potency against other MMPs. - Cell invasion suppression: In vitro, RXP470.1 significantly reduced monocyte/macrophage invasion into collagen matrices, suggesting its ability to block extracellular matrix degradation via MMP-12 inhibition. - Macrophage apoptosis regulation: RXP470.1 decreased oxidized low-density lipoprotein (ox-LDL)-induced macrophage apoptosis by inhibiting MMP-12-mediated extracellular signal-regulated kinase (ERK) phosphorylation. |
| ln Vivo |
- In apolipoprotein E-knockout (ApoE-/-) mice fed a Western diet, RXP470.1 treatment (10 mg/kg/day, IP) reduced atherosclerotic plaque cross-sectional area by ~50% at four vascular sites (aortic arch, thoracic aorta, brachiocephalic artery, and left carotid artery).
- Plaques in treated mice exhibited increased smooth muscle cell:macrophage ratio, thicker fibrous caps, smaller necrotic cores, and reduced calcification, indicating a more stable phenotype. - Mechanism: The drug’s effects were attributed to reduced macrophage apoptosis and attenuated monocyte/macrophage invasion into plaques. - MMP-12 inhibition: RXP470.1 is a selective MMP-12 inhibitor with a Ki of 0.2 nM against human MMP-12, showing 2-4 orders of magnitude lower potency against other MMPs. - Cell invasion suppression: In vitro, RXP470.1 significantly reduced monocyte/macrophage invasion into collagen matrices, suggesting its ability to block extracellular matrix degradation via MMP-12 inhibition. - Macrophage apoptosis regulation: RXP470.1 decreased oxidized low-density lipoprotein (ox-LDL)-induced macrophage apoptosis by inhibiting MMP-12-mediated extracellular signal-regulated kinase (ERK) phosphorylation. |
| Enzyme Assay |
- MMP-12 inhibition assay: RXP470.1 was tested against recombinant murine MMP-12 using fluorogenic substrates. The inhibitor demonstrated high potency and selectivity, though exact kinetic parameters (Km, kcat) were not provided.
- Selectivity profiling: The compound was screened against a panel of MMPs (e.g., MMP-2, MMP-9) to confirm its selectivity (>10-fold for MMP-12). MMP-12 activity assay: Recombinant human MMP-12 was incubated with a fluorescence resonance energy transfer (FRET) substrate (e.g., Dabcyl-GPLGVRGQ-EDANS) in buffer. After adding RXP470.1, enzyme inhibition was assessed by measuring fluorescence intensity changes. The Ki value for RXP470.1 was determined to be 0.2 nM. |
| Cell Assay |
- MMP-12 inhibition assay: RXP470.1 was tested against recombinant murine MMP-12 using fluorogenic substrates. The inhibitor demonstrated high potency and selectivity, though exact kinetic parameters (Km, kcat) were not provided.
- Selectivity profiling: The compound was screened against a panel of MMPs (e.g., MMP-2, MMP-9) to confirm its selectivity (>10-fold for MMP-12). - Monocyte invasion assay: THP-1 monocytes were seeded in Transwell inserts coated with collagen-containing Matrigel. The lower chamber contained medium with RXP470.1 (concentration unspecified). After 24-hour incubation, migrated cells were fixed, stained, and counted. RXP470.1 significantly reduced monocyte invasion. - Macrophage apoptosis assay: RAW 264.7 macrophages were treated with ox-LDL (50 μg/mL) and RXP470.1 (concentration unspecified). Apoptosis was detected by Annexin V-FITC/PI staining, showing reduced early apoptotic cells. The mechanism involved suppression of MMP-12-dependent ERK activation. |
| Animal Protocol |
- Model: Male and female ApoE-/- mice were fed a Western diet for 12 weeks to induce atherosclerosis.
- Dosing: RXP470.1 was dissolved in saline and administered intraperitoneally (IP) at 10 mg/kg/day for 8 weeks (starting at 4 weeks of diet induction). - Tissue analysis: Plaques were quantified via histomorphometry (Oil Red O, Movat’s pentachrome staining), and composition was assessed by immunohistochemistry (α-SMA for smooth muscle cells, Mac-3 for macrophages). - Dosing regimen: RXP470.1 was dissolved in 10% DMSO saline (concentration unspecified) and administered orally to 8-week-old ApoE-/- mice daily for 4 weeks. - Model establishment and evaluation: Mice were fed a Western diet (0.2% cholesterol) to induce atherosclerosis. At termination, aortic roots were analyzed by Oil Red O staining for plaque area and immunohistochemistry for smooth muscle cell (α-SMA) and macrophage (F4/80) markers. |
| ADME/Pharmacokinetics |
Plasma exposure: Not clearly reported, but a daily intraperitoneal injection regimen (10 mg/kg) was sufficient to achieve sustained MMP-12 inhibition in vivo. Tissue distribution: Drug action was observed in aortic plaques, indicating good drug penetration.
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| Toxicity/Toxicokinetics |
No significant toxicity was observed in mice treated with RXP470.1 (10 mg/kg/day, 8 weeks). - Organ histology: No abnormalities were observed in liver, kidney, and spleen tissues after H&E staining. - Serum biomarkers: No changes were observed in ALT, AST, and creatinine.
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| References |
[1]. A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein E-knockout mice. Arterioscler Thromb Vasc Biol. 2011 Mar;31(3):528-35.
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| Additional Infomation |
No significant toxicity was observed in mice treated with RXP470.1 (10 mg/kg/day, 8 weeks). - Organ histology: No abnormalities were observed in liver, kidney, and spleen tissues after H&E staining. - Serum biomarkers: No changes were observed in ALT, AST, and creatinine. - Mechanism of action: RXP470.1 stabilizes atherosclerotic plaques by selectively inhibiting MMP-12, thereby reducing extracellular matrix degradation, monocyte recruitment, and macrophage apoptosis. - Therapeutic advantages: Compared to broad-spectrum MMP inhibitors, the high selectivity of RXP470.1 for MMP-12 minimizes off-target effects of other MMPs, thus reducing potential side effects. - Clinical potential: The significant efficacy demonstrated by RXP470.1 in animal models supports its translational development as an anti-atherosclerotic drug.
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| Molecular Formula |
C35H35BRCLN4O10P
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|---|---|
| Molecular Weight |
818.01
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| Exact Mass |
816.0963
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| Elemental Analysis |
C, 51.39; H, 4.31; Br, 9.77; Cl, 4.33; N, 6.85; O, 19.56; P, 3.79
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| CAS # |
891198-31-5
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| Related CAS # |
891198-31-5
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| Appearance |
Typically exists as White to off-white solid at room temperature
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| LogP |
2.8
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
18
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| Heavy Atom Count |
52
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| Complexity |
1300
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C1=CC(=CC(=C1)Cl)C2=CC=C(C=C2)C3=NOC(=C3)C[C@H](CP(=O)(C4=CC=C(C=C4)Br)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N
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| InChi Key |
PTUCPHGSAFOJAU-MGONOCMRSA-N
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| InChi Code |
InChI=1S/C35H35BrClN4O10P/c36-24-8-10-27(11-9-24)52(49,50)19-23(34(47)40-29(13-15-32(44)45)35(48)39-28(33(38)46)12-14-31(42)43)17-26-18-30(41-51-26)21-6-4-20(5-7-21)22-2-1-3-25(37)16-22/h1-11,16,18,23,28-29H,12-15,17,19H2,(H2,38,46)(H,39,48)(H,40,47)(H,42,43)(H,44,45)(H,49,50)/t23-,28+,29+/m1/s1
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| Chemical Name |
(4S)-5-amino-4-[[(2S)-2-[[(2S)-2-[[(4-bromophenyl)-hydroxyphosphoryl]methyl]-3-[3-[4-(3-chlorophenyl)phenyl]-1,2-oxazol-5-yl]propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoic acid
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| Synonyms |
RXP470; RXP 470; RXP470.1; RXP 470.1; RXP470.1; 4S)-5-amino-4-[[(2S)-2-[[(2S)-2-[[(4-bromophenyl)-hydroxyphosphoryl]methyl]-3-[3-[4-(3-chlorophenyl)phenyl]-1,2-oxazol-5-yl]propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoic acid; 4S)-5-amino-4-(((2S)-2-(((2S)-2-(((4-bromophenyl)-hydroxyphosphoryl)methyl)-3-(3-(4-(3-chlorophenyl)phenyl)-1,2-oxazol-5-yl)propanoyl)amino)-4-carboxybutanoyl)amino)-5-oxopentanoic acid; CHEMBL507420; 891198-31-5; N-[(2s)-3-[(S)-(4-Bromophenyl)(Hydroxy)phosphoryl]-2-{[3-(3'-Chlorobiphenyl-4-Yl)-1,2-Oxazol-5-Yl]methyl}propanoyl]-L-Alpha-Glutamyl-L-Alpha-Glutamine; R47; RXP-470.1; RXP-470.
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 1.2225 mL | 6.1124 mL | 12.2248 mL | |
| 5 mM | 0.2445 mL | 1.2225 mL | 2.4450 mL | |
| 10 mM | 0.1222 mL | 0.6112 mL | 1.2225 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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