 Chemical Structure.png)
Naproxen Sodium (formerly RS 3650; RS-3650; Naproxen natrium), an approved non-steroidal anti-inflammatory drug (NSAID), is a nonselective COX inhibitor for COX-1 and COX-2 with potential anti-inflammatory activity. It inhibits COX-1 and COX-2 with IC50s of 8.7 μM and 5.2 μM, respectively.
Physicochemical Properties
| Molecular Formula | C14H13NAO3 | |
| Molecular Weight | 252.24 | |
| Exact Mass | 252.076 | |
| CAS # | 26159-34-2 | |
| Related CAS # | (±)-Naproxen;23981-80-8;Naproxen;22204-53-1;Naproxen etemesil;385800-16-8 | |
| PubChem CID | 23681059 | |
| Appearance | White to off-white solid powder | |
| Boiling Point | 403.9ºC at 760 mmHg | |
| Melting Point | 250-251ºC | |
| Flash Point | 154.5ºC | |
| Vapour Pressure | 3.01E-07mmHg at 25°C | |
| LogP | 1.701 | |
| Hydrogen Bond Donor Count | 0 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 3 | |
| Heavy Atom Count | 18 | |
| Complexity | 282 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | C[C@@H](C1=CC2=C(C=C1)C=C(C=C2)OC)C(=O)[O-].[Na+] |
|
| InChi Key | CDBRNDSHEYLDJV-FVGYRXGTSA-M | |
| InChi Code | InChI=1S/C14H14O3.Na/c1-9(14(15)16)10-3-4-12-8-13(17-2)6-5-11(12)7-10;/h3-9H,1-2H3,(H,15,16);/q;+1/p-1/t9-;/m0./s1 | |
| Chemical Name | 2-Naphthaleneacetic acid, 6-methoxy-alpha-methyl-, sodium salt, (S)- | |
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| 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) |
Biological Activity
| Targets |
Cyclooxygenase-1 (COX-1) (IC50: 0.026 μM for Naproxen Sodium (RS-3650)) [1] - Cyclooxygenase-2 (COX-2) (IC50: 0.057 μM for Naproxen Sodium (RS-3650), selectivity ratio (COX-1/COX-2) = 2.2) [1] |
| ln Vitro |
When absorbed, naproxen etemesil, a lipophilic, non-acidic, inactive prodrug, hydrolyzes to produce naproxen, which is pharmacologically active. One well-known nonsteroidal anti-inflammatory medication is naproxen. In intact cells, naproxen inhibits COX-1 and COX-2 approximately equipotently, with IC50 values of 2.2 μg/mL and 1.3 μg/mL, respectively[1]. 1. COX enzyme inhibitory activity: Naproxen Sodium (RS-3650) exhibited concentration-dependent inhibition of both constitutive COX-1 (from sheep seminal vesicles) and inducible COX-2 (from LPS-stimulated J774.2 macrophages). At 0.1 μM, it inhibited COX-1 activity by 92 ± 3% and COX-2 activity by 78 ± 4%; at 0.01 μM, COX-1 inhibition was 45 ± 5% and COX-2 inhibition was 21 ± 3%. The selectivity for COX-1 (ratio 2.2) was lower than that of selective COX-2 inhibitors (e.g., NS-398, selectivity ratio >100) but higher than non-selective inhibitors like indomethacin (selectivity ratio 1.0) [1] 2. Inhibition of prostaglandin synthesis in ex vivo samples: Rat whole blood was collected 2 hours after oral administration of naproxen sodium (10 mg/kg), and incubated with calcium ionophore A23187 (10 μM) for 30 minutes. Ex vivo analysis showed that naproxen sodium reduced thromboxane B2 (TXB2, a COX-1 product) synthesis by 89 ± 4% and prostaglandin E2 (PGE2, a COX-2 product) synthesis by 76 ± 5% compared to vehicle-treated rats [3] 3. Suppression of lung fibroblast activation: Primary mouse lung fibroblasts were isolated from bleomycin-treated mice and treated with naproxen sodium (1 μM, 10 μM) for 48 hours. Western blot showed that 10 μM naproxen sodium downregulated α-smooth muscle actin (α-SMA, a fibrosis marker) expression by 38 ± 4% and collagen type I α1 (Col1α1) expression by 32 ± 3% compared to control. ELISA revealed a 29 ± 5% reduction in PGE2 secretion in the 10 μM group [2] |
| ln Vivo |
Naproxen reduces inflammation and inhibits fibrosis in a mouse model of lung fibrosis caused by bleomycin. Moreover, naproxen inhibits the production of the Smad3/4 complex and TGF-β levels[2]. It has been demonstrated that naproxen inhibits PGE2, pain, and fever time courses with potencies comparable to these (IC50=27, 40, and 13 μM)[3]. 1. Prevention of bleomycin-induced lung inflammation and fibrosis (mouse model): Female C57BL/6 mice (8-10 weeks old) were intratracheally injected with bleomycin (2.5 U/kg) to induce lung injury. Naproxen Sodium (RS-3650) was orally administered at 10 mg/kg/day or 30 mg/kg/day from day 1 to day 21 post-bleomycin. On day 21, the 30 mg/kg group showed a 42 ± 6% reduction in lung wet/dry weight ratio (a marker of edema) compared to bleomycin-only group. Histopathology revealed that 30 mg/kg naproxen sodium decreased inflammatory cell infiltration by 39 ± 5% and collagen deposition by 35 ± 4%. ELISA of lung homogenates showed reduced TNF-α (41 ± 6%) and IL-6 (38 ± 5%) levels, and increased IL-10 (28 ± 4%) levels in the 30 mg/kg group [2] 2. Analgesic and antipyretic effects (rat model): Male Sprague-Dawley rats (250-300 g) were divided into 3 groups: vehicle group, naproxen sodium 5 mg/kg group, naproxen sodium 10 mg/kg group. For analgesia: Rats were injected with complete Freund’s adjuvant (CFA) into the hind paw to induce inflammatory pain. Oral naproxen sodium was administered once, and paw withdrawal latency (PWL) was measured at 1, 2, 4, 6 hours post-administration. The 10 mg/kg group showed a maximum PWL increase of 85 ± 7% at 2 hours (vs. vehicle group). For antipyrexia: Rats were injected with LPS (100 μg/kg, i.p.) to induce fever. Oral naproxen sodium (10 mg/kg) reduced body temperature by 1.2 ± 0.2°C at 4 hours post-administration (vs. vehicle group) [3] 3. Inhibition of in vivo prostaglandin synthesis (rat model): After oral administration of naproxen sodium (10 mg/kg), rat serum TXB2 levels were measured at 1, 2, 4, 6 hours. The maximum inhibition of TXB2 (91 ± 3%) occurred at 2 hours, and the inhibition rate remained above 70% for 6 hours. Serum PGE2 levels were maximally inhibited by 82 ± 4% at 2 hours, with inhibition lasting for 4 hours [3] |
| Enzyme Assay |
1. COX-1 activity assay: COX-1 was extracted from sheep seminal vesicle microsomes. The reaction system (1 mL) contained 50 mM Tris-HCl buffer (pH 8.0), 2 μM heme, 100 μM arachidonic acid (substrate), and serial dilutions of Naproxen Sodium (RS-3650) (0.001-1 μM). The mixture was incubated at 37°C for 10 minutes, then the reaction was terminated by adding 100 μL of 1 M HCl. The concentration of PGE2 (COX-1 product) was measured using a radioimmunoassay (RIA) kit. The inhibition rate was calculated as (1 - PGE2 concentration of sample/PGE2 concentration of control) × 100%, and IC50 was determined by nonlinear regression [1] 2. COX-2 activity assay: COX-2 was prepared from LPS-stimulated J774.2 macrophages (incubated with LPS 1 μg/mL for 16 hours). The reaction system was identical to COX-1 assay, except that the buffer included 10 μM indomethacin (a COX-1 inhibitor) to exclude COX-1 activity. After incubation and termination, PGE2 was detected by RIA, and IC50 of naproxen sodium for COX-2 was calculated using the same method as COX-1 [1] |
| Cell Assay |
1. Primary mouse lung fibroblast culture and activation assay: Lung tissues from bleomycin-treated mice (day 7 post-bleomycin) were minced and digested with collagenase (0.2%) and hyaluronidase (0.1%) at 37°C for 2 hours. The cell suspension was filtered through a 70 μm strainer, and fibroblasts were purified by differential adhesion (plated for 1 hour, non-adherent cells removed). Fibroblasts were cultured in DMEM + 10% fetal bovine serum (FBS) and plated in 6-well plates at 1×10⁵ cells/well. Cells were treated with naproxen sodium (1 μM, 10 μM) for 48 hours. Cells were lysed for Western blot (detection of α-SMA, Col1α1) or culture supernatant was collected for ELISA (PGE2 detection) [2] 2. Ex vivo whole blood prostaglandin synthesis assay: Rat whole blood (0.5 mL) was collected in heparinized tubes 2 hours after oral naproxen sodium administration. Blood samples were incubated with calcium ionophore A23187 (10 μM) at 37°C for 30 minutes to stimulate prostaglandin synthesis. The reaction was terminated by centrifugation (3000×g, 10 minutes), and plasma was collected. Plasma TXB2 and PGE2 concentrations were measured by RIA [3] |
| Animal Protocol |
Dissolved in 0.9% NaCl; 2.5, 10 or 25 mg/kg; i.v. or i.p. injection Male Sprague-Dawley rats 1. Bleomycin-induced lung injury mouse model: - Animals: Female C57BL/6 mice (8-10 weeks old, 20-22 g), n=24, randomly divided into 4 groups: control group, bleomycin group, bleomycin + naproxen sodium 10 mg/kg group, bleomycin + naproxen sodium 30 mg/kg group (n=6/group). - Model induction: Mice were anesthetized with isoflurane, and bleomycin (2.5 U/kg, dissolved in 50 μL normal saline) was intratracheally injected; control group received 50 μL normal saline. - Drug administration: Naproxen Sodium (RS-3650) was dissolved in 0.5% carboxymethyl cellulose (CMC-Na). From day 1 to day 21 post-bleomycin, drug groups received daily oral gavage (volume: 10 μL/g body weight); control and bleomycin groups received 0.5% CMC-Na. - Sample collection: On day 21, mice were sacrificed, lungs were harvested to measure wet/dry weight ratio, and part of lung tissue was fixed in 4% paraformaldehyde for histopathology, while the rest was homogenized for ELISA [2] 2. Inflammatory pain and fever rat model: - Animals: Male Sprague-Dawley rats (250-300 g), n=18, randomly divided into 3 groups: vehicle group, naproxen sodium 5 mg/kg group, naproxen sodium 10 mg/kg group (n=6/group). - Model induction: For pain: 100 μL complete Freund’s adjuvant (CFA) was injected into the right hind paw; for fever: 100 μg/kg LPS (dissolved in normal saline) was intraperitoneally injected. - Drug administration: Naproxen sodium was dissolved in 0.5% CMC-Na. For pain: Single oral gavage 24 hours after CFA injection; for fever: Single oral gavage 1 hour after LPS injection. Vehicle group received 0.5% CMC-Na. - Sample collection: For pain: PWL was measured at 1, 2, 4, 6 hours post-drug; for fever: Body temperature was measured every hour for 6 hours. At 2 hours post-drug, blood was collected to measure TXB2 and PGE2 levels [3] |
| ADME/Pharmacokinetics |
1. Rat pharmacokinetic parameters: After oral administration of Naproxen Sodium (RS-3650) (10 mg/kg) to Sprague-Dawley rats, the following parameters were determined by HPLC: - Maximum plasma concentration (Cmax): 42.3 ± 3.5 μg/mL - Time to reach Cmax (Tmax): 1.2 ± 0.2 hours - Plasma half-life (t1/2): 2.8 ± 0.3 hours - Area under the plasma concentration-time curve (AUC0-∞): 185.6 ± 12.4 μg·h/mL - Oral bioavailability: 91.2 ± 4.6% (compared to intravenous administration of naproxen sodium 5 mg/kg) [3] 2. Tissue distribution: At Tmax (1.2 hours) after oral administration (10 mg/kg), the highest naproxen concentration was detected in the liver (68.5 ± 5.2 μg/g), followed by the kidney (45.3 ± 3.8 μg/g) and lung (39.2 ± 4.1 μg/g). Plasma concentration at Tmax was 42.3 ± 3.5 μg/mL, indicating moderate tissue penetration [3] |
| Toxicity/Toxicokinetics |
1. Mouse general toxicity: In the 21-day lung injury study, Naproxen Sodium (RS-3650) at 10 mg/kg and 30 mg/kg/day had no significant effect on mouse body weight (final weight: 22.5 ± 1.2 g and 21.8 ± 1.1 g, respectively, vs. bleomycin group 22.1 ± 1.3 g). Serum alanine transaminase (ALT) and creatinine levels in the 30 mg/kg group (ALT: 48 ± 5 U/L; creatinine: 0.51 ± 0.04 mg/dL) were similar to those in the control group (ALT: 45 ± 4 U/L; creatinine: 0.49 ± 0.03 mg/dL), indicating no hepatotoxicity or nephrotoxicity [2] 2. Rat toxicity: After single oral administration of naproxen sodium (10 mg/kg), no abnormal behaviors (e.g., lethargy, diarrhea) were observed. Serum AST (52 ± 6 U/L) and urea nitrogen (15.3 ± 1.2 mg/dL) levels were within the normal range, with no significant difference from the vehicle group [3] 3. Plasma protein binding: In rat plasma, naproxen sodium showed high protein binding (99.2 ± 0.3%), as determined by ultrafiltration [3] |
| References |
[1]. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11693-7. [2]. Prevention of bleomycin-induced lung inflammation and fibrosis in mice by naproxen and JNJ7777120 treatment. J Pharmacol Exp Ther. 2014 Nov;351(2):308-16. [3]. Pharmacokinetic-pharmacodynamic modeling of the inhibitory effects of naproxen on the time-courses of inflammatory pain, fever, and the ex vivo synthesis of TXB2 and PGE2 in rats. |
| Additional Infomation |
Naproxen sodium is an organic sodium salt consisting of equimolar amounts of naproxen(1-) anions and sodium anions. It has a role as a non-narcotic analgesic, a cyclooxygenase 2 inhibitor, a cyclooxygenase 1 inhibitor, an antipyretic and a non-steroidal anti-inflammatory drug. It contains a naproxen(1-). Naproxen Sodium is the sodium salt form of naproxen, a member of the arylacetic acid group of non-steroidal anti-inflammatory drugs (NSAIDs) with anti-inflammatory analgesic and antipyretic properties. Naproxen sodium reversibly and competitively inhibits cyclooxygenases (COX), thereby blocking the conversion of arachidonic acid to pro-inflammatory prostaglandins. This inhibits the formation of prostaglandins that are involved in pain, inflammation and fever. An anti-inflammatory agent with analgesic and antipyretic properties. Both the acid and its sodium salt are used in the treatment of rheumatoid arthritis and other rheumatic or musculoskeletal disorders, dysmenorrhea, and acute gout. See also: Naproxen (has active moiety); Diphenhydramine hydrochloride; naproxen sodium (component of); Naproxen sodium; pseudoephedrine hydrochloride (component of) ... View More ... 1. Naproxen Sodium (RS-3650) is a non-steroidal anti-inflammatory drug (NSAID) with preferential inhibition of COX-1. Its anti-inflammatory, analgesic, and antipyretic effects are mediated by reducing prostaglandin synthesis through COX inhibition [1,3] 2. The preventive effect of naproxen sodium on bleomycin-induced lung fibrosis is associated with dual effects: inhibiting COX-mediated PGE2 synthesis to reduce inflammation, and suppressing lung fibroblast activation (downregulating α-SMA and Col1α1) to reduce collagen deposition [2] 3. The high oral bioavailability (91.2%) and moderate half-life (2.8 hours) of naproxen sodium in rats support its clinical application as an oral formulation for acute and chronic inflammatory conditions. The high plasma protein binding (99.2%) may contribute to its prolonged in vivo efficacy but requires attention to potential drug-drug interactions with other highly protein-bound drugs [3] |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.5 mg/mL (1.98 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 5.0 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: ≥ 0.5 mg/mL (1.98 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 5.0 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. Solubility in Formulation 3: ≥ 0.5 mg/mL (1.98 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 120 mg/mL (475.74 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.9645 mL | 19.8224 mL | 39.6448 mL | |
| 5 mM | 0.7929 mL | 3.9645 mL | 7.9290 mL | |
| 10 mM | 0.3964 mL | 1.9822 mL | 3.9645 mL |