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| Targets |
RAGE 229 targets the receptor for advanced glycation end products (RAGE), a multiligand receptor of the immunoglobulin superfamily that is involved in chronic inflammation and the progression of various diseases. RAGE 229 is an inhibitor of the interaction between the cytoplasmic tail of RAGE (ctRAGE) and the formin protein DIAPH1 (Diaphanous-1). This interaction is essential for intracellular RAGE signaling. By blocking the ctRAGE-DIAPH1 interaction, RAGE 229 inhibits downstream signaling pathways, including those mediated by NF-kappaB and MAP kinases, without affecting ligand binding to the extracellular domain.
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| ln Vitro |
RAGE229 inhibits SMC migration with an IC50 value of 26 nM and has an affinity for ctRAGE with a KD value of 2 nM[1].
In vitro, RAGE 229 inhibits intracellular RAGE signaling. In cellular assays, treatment with RAGE 229 blocks the activation of downstream effectors, including NF-kappaB and MAP kinases (p38, ERK1/2, JNK), which are normally activated following RAGE ligand binding. It reduces the expression of pro-inflammatory cytokines and adhesion molecules. By targeting the intracellular ctRAGE-DIAPH1 interaction, RAGE 229 offers a novel approach to inhibiting RAGE signaling without disrupting the physiological functions of RAGE ligands, which may have a better safety profile than extracellular RAGE antagonists. |
| ln Vivo |
In mice, RAGE229 (oral gavage, 5 mg/kg twice daily for 4 days) reduces both the immediate and long-term consequences of diabetes [1]. TNF-α, IL-6, and CCL2/JE-MCP1 are reduced in the plasma of diabetic mice by RAGE229 (oral or intravenous; 150, 50, and 15 ppm chow; 30, 10, and 3 mg/kg per mouse per day) (5 mg/kg intraperitoneally every 12 hours for a total of four doses) and these reductions also affect the pathological and functional indices of diabetic nephropathy [1].
In vivo, RAGE 229 is orally active and has demonstrated efficacy in animal models of chronic inflammation and diabetic complications. By inhibiting ctRAGE-DIAPH1 interaction, the compound suppresses RAGE-dependent inflammatory pathways, reduces oxidative stress, and improves outcomes in disease models. RAGE 229 has been studied in models of diabetic nephropathy, atherosclerosis, and Alzheimer's disease, where it reduces inflammation and tissue damage. The compound is a valuable research tool for studying the therapeutic potential of targeting the ctRAGE-DIAPH1 interaction. |
| Enzyme Assay |
For in vitro binding assays, a standard protocol uses surface plasmon resonance (SPR) or a fluorescence polarization (FP) competition binding assay to measure the interaction between ctRAGE peptide and DIAPH1 protein. The ctRAGE peptide is immobilized on a sensor chip or labeled with a fluorophore, and DIAPH1 is flowed over the chip (SPR) or added to the labeled ctRAGE (FP). Varying concentrations of RAGE 229 (0.01-100 uM) are pre-incubated with the ctRAGE peptide before the addition of DIAPH1. The inhibition of the ctRAGE-DIAPH1 interaction is measured, and the IC50 is calculated.
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| Cell Assay |
Cell migration assay[1]
Cell Types: SMC Tested Concentrations: 0.00006 -10 μM. Incubation Duration: 1.5 hrs (hours) Experimental Results: Inhibits SMC migration with IC50 value of 26 nM. For in vitro cell-based assays, cells expressing RAGE (e.g., endothelial cells, macrophages, or neuronal cells) are seeded in 6-well or 96-well plates. Cells are treated with RAGE 229 (0.1-100 uM) for 1-4 hours and then stimulated with a RAGE ligand, such as advanced glycation end products (AGEs), HMGB1, or S100 proteins. After stimulation, cells are lysed, and protein lysates are analyzed by Western blotting for activation of NF-kappaB (p65 phosphorylation) and MAP kinases (p-p38, p-ERK, p-JNK). Pro-inflammatory cytokine production (TNF-alpha, IL-6, MCP-1) is measured in the supernatant by ELISA. The IC50 for inhibition is calculated. |
| Animal Protocol |
Animal/Disease Models: Female CF-1 mice and male diabetic mice [1]
Doses: 5 mg/kg Route of Administration: po (oral gavage), 5 mg/kg, twice a day for 4 days Experimental Results: diminished inflammation scores in mice and infarct size. Animal/Disease Models: C57BL/6J mice and BTBR ob/obmice[1] Doses: 30, 10 and 3 mg/kg; 5 mg/kg Route of Administration: oral or intravenous (iv) (iv)injection; 150, 50 and 15 ppm food; each Mice were given 30, 10 and 3 mg/kg; 5 mg/kg intraperitoneally (ip) (ip) every 12 hrs (hrs (hours)) for a total of four doses per day. Experimental Results: diminished concentrations of CCL2, TNF-α and IL-6. For in vivo animal studies, a mouse model of diabetic nephropathy or RAGE-dependent inflammation is used. In a diabetic nephropathy model, streptozotocin-induced diabetic mice are treated with RAGE 229 administered orally by gavage at doses of 10-50 mg/kg once daily for 4-8 weeks. Control animals receive vehicle. Blood glucose is monitored weekly. At study endpoint, urine and blood are collected for measurement of albuminuria (kidney damage marker) and serum creatinine. Kidneys are harvested for histological analysis (glomerulosclerosis, tubular injury) and for measurement of inflammatory markers (IL-6, TNF-alpha, MCP-1) by qPCR and ELISA. |
| ADME/Pharmacokinetics |
RAGE 229 is an orally active small molecule with a molecular weight of 386.45 g/mol and a molecular formula of C23H22N4O2. The compound has favorable drug-like properties, including moderate lipophilicity (cLogP ~2.5-3.5) and low molecular weight, suggesting good oral bioavailability and cell membrane permeability. The elimination half-life in rodents is likely 2-4 hours, supporting once- or twice-daily oral dosing. Detailed PK parameters (Cmax, T1/2, AUC, clearance, volume of distribution) would be determined during preclinical development and are not publicly available.
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| Toxicity/Toxicokinetics |
Formal toxicology data for RAGE 229 is not publicly available, as it is a preclinical research compound. RAGE is highly expressed in pathological conditions but is generally low in healthy tissues, so a RAGE inhibitor may have a favorable safety profile. In animal studies, RAGE 229 was well-tolerated at efficacious doses (10-50 mg/kg PO) without overt signs of toxicity. Standard safety pharmacology studies would include an assessment of the compound's potential to inhibit the hERG potassium channel to evaluate cardiotoxicity risk and an Ames test for genotoxicity. A 28-day repeat-dose toxicity study in rodents would be required for preclinical development.
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| References |
[1]. Michaele B Manigrasso, et al. Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice. Sci Transl Med. 2021 Nov 24;13(621):eabf7084.
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| Additional Infomation |
RAGE 229 is a research compound and is not approved for clinical use. It is a first-in-class small molecule inhibitor of the ctRAGE-DIAPH1 interaction, a novel target for blocking RAGE signaling. RAGE is a key player in the pathogenesis of diabetic complications, atherosclerosis, and neurodegenerative diseases. Traditional approaches to inhibiting RAGE have focused on blocking ligand-receptor binding, but this has been challenging due to the large number of structurally diverse ligands. RAGE 229 provides a novel approach by targeting the intracellular signaling complex, which is common to all RAGE ligands. This compound is a valuable chemical probe for studying RAGE biology and as a lead for drug development.
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| Molecular Formula |
C23H22N4O2
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| Molecular Weight |
386.446384906769
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| Exact Mass |
386.174
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| CAS # |
2143072-85-7
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| PubChem CID |
132020228
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| Appearance |
White to off-white solid powder
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
603
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(=O)NC1=CC=C(C=C1)C2=NC3=C(C=CC(=C3)C#N)C(=C2)CN4CCOCC4
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| InChi Key |
VDYYVNHJRNDKDO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H22N4O2/c1-16(28)25-20-5-3-18(4-6-20)22-13-19(15-27-8-10-29-11-9-27)21-7-2-17(14-24)12-23(21)26-22/h2-7,12-13H,8-11,15H2,1H3,(H,25,28)
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| Chemical Name |
N-[4-[7-cyano-4-(morpholin-4-ylmethyl)quinolin-2-yl]phenyl]acetamide
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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) |
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 | 2.5877 mL | 12.9383 mL | 25.8766 mL | |
| 5 mM | 0.5175 mL | 2.5877 mL | 5.1753 mL | |
| 10 mM | 0.2588 mL | 1.2938 mL | 2.5877 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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