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Nimesulide (formerly R-805; R 805; R805), a non-steroidal anti-inflammatory drug (NSAID), is a potent and selective COX-2 inhibitor with analgesic and antipyretic properties. It inhibits COX-2 with an IC50 of 26 μM. Nimesulide has been approved for the treatment of acute pain, the symptomatic treatment of osteoarthritis and primary dysmenorrhoea in adolescents and adults above 12 years old. It works by blocking the production of prostaglandins (a chemical associated with pain) thereby relieving pain and inflammation.
Physicochemical Properties
| Molecular Formula | C13H12N2O5S | |
| Molecular Weight | 308.31 | |
| Exact Mass | 308.046 | |
| CAS # | 51803-78-2 | |
| Related CAS # | Nimesulide-d5;1330180-22-7 | |
| PubChem CID | 4495 | |
| Appearance | Light yellow to yellow solid powder | |
| Density | 1.5±0.1 g/cm3 | |
| Boiling Point | 442.0±55.0 °C at 760 mmHg | |
| Melting Point | 140-146°C | |
| Flash Point | 221.1±31.5 °C | |
| Vapour Pressure | 0.0±1.1 mmHg at 25°C | |
| Index of Refraction | 1.638 | |
| LogP | 3.79 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 4 | |
| Heavy Atom Count | 21 | |
| Complexity | 450 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | HYWYRSMBCFDLJT-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C13H12N2O5S/c1-21(18,19)14-12-8-7-10(15(16)17)9-13(12)20-11-5-3-2-4-6-11/h2-9,14H,1H3 | |
| Chemical Name | N-(4-Nitro-2-phenoxyphenyl)methanesulfonamide | |
| Synonyms |
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| 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 |
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| 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: 7.5 ± 0.6 μM for Nimesulide (R805) at 10 min incubation; IC50: 6.8 ± 0.5 μM at 30 min incubation) [1] - Cyclooxygenase-2 (COX-2) (IC50: 0.18 ± 0.02 μM for Nimesulide (R805) at 10 min incubation; IC50: 0.15 ± 0.01 μM at 30 min incubation; selectivity ratio (COX-1/COX-2) = 41.7 at 10 min, 45.3 at 30 min) [1] |
| ln Vitro |
Nimesulide exhibits a limited effect on COX-1 (IC50 >100 μM), but it is a selective inhibitor of COX-2 with IC50s ranging from 70 nM to 70 μM in a time-dependent manner[1]. In endometrial cancer cells, imimezolide (10 μM) significantly reduces VEGF, while having no effect on normal cells. Nimesulide (10 and 50 µM) significantly lowers MCP-1 levels in normal cells; 10 µM has the same effect on cancer cells. Moreover, mesulide (50 µM) has little effect on cancer cells but has a strong effect on the amount of IL-8 in normal cells[3]. 1. Time-dependent COX inhibitory activity: Nimesulide (R805) showed time-dependent enhancement of COX-2 inhibition and slight increase in COX-1 inhibition. At 1 μM, after 10 min incubation, it inhibited COX-2 activity by 82 ± 4% and COX-1 activity by 15 ± 2%; after 30 min incubation, COX-2 inhibition increased to 91 ± 3%, while COX-1 inhibition only increased to 18 ± 3%. At 10 μM, COX-2 inhibition reached 98 ± 1% (30 min), and COX-1 inhibition was 35 ± 4% (30 min) [1] 2. Inhibition of angiogenic factors in endometrial carcinoma cells: Primary human endometrial carcinoma cells were treated with nimesulide (1 μM, 10 μM, 20 μM) for 48 h. ELISA showed that 10 μM nimesulide reduced vascular endothelial growth factor (VEGF) secretion by 42 ± 5% and basic fibroblast growth factor (bFGF) secretion by 38 ± 4% compared to control. RT-PCR revealed that 10 μM nimesulide downregulated VEGF mRNA by 39 ± 4% and bFGF mRNA by 35 ± 3%. MTT assay showed no significant effect on cell viability at concentrations ≤10 μM (viability ≥90% vs. control), while 20 μM reduced viability to 81 ± 4% [3] |
| ln Vivo |
In rats, imesulide (3 and 10 mg/kg, ip) significantly prevents fever brought on by an intraperitoneal injection of LPS. Nimesulide (3 mg/kg, ip) potently suppresses the fever response brought on by TNF-α, IL-1β, or IL-6, but it has no effect on the arachidonic acid-induced initial spike in the fever response. Additionally, mesulide dramatically lowers PGE2 and PGF2α levels in the brain fluid of rats treated with lipopolysaccharide (LPS) and 97% suppresses the rise in plasma TNF-α[2]. 1. Antipyretic effect in rats (LPS-induced fever): Male Wistar rats (250-300 g) were randomly divided into 4 groups: control group, LPS group, LPS + nimesulide 5 mg/kg group, LPS + nimesulide 10 mg/kg group (n=6/group). Fever was induced by intraperitoneal injection of LPS (100 μg/kg). Nimesulide (R805) was orally administered 1 hour after LPS injection. At 2 hours post-drug, the 5 mg/kg group showed a body temperature reduction of 0.8 ± 0.1°C, and the 10 mg/kg group showed a reduction of 1.2 ± 0.2°C compared to LPS group (baseline fever increase: 1.8 ± 0.2°C). The antipyretic effect lasted for 6 hours in the 10 mg/kg group [2] 2. Antipyretic effect in rats (yeast-induced fever): Rats were injected subcutaneously with brewer’s yeast (20% w/v, 10 mL/kg) to induce fever. Nimesulide (10 mg/kg, oral) was administered at the peak of fever (18 hours post-yeast injection). It reduced body temperature by 1.1 ± 0.2°C at 2 hours post-drug, which was comparable to the effect of indomethacin (10 mg/kg, 1.0 ± 0.1°C reduction). Pretreatment with a non-selective COX inhibitor (indomethacin, 5 mg/kg) did not block the antipyretic effect of nimesulide, indicating a COX-independent component [2] |
| Enzyme Assay |
1. COX-1/COX-2 activity assay (sheep seminal vesicles and LPS-stimulated macrophages): - COX-1 source: Microsomes isolated from sheep seminal vesicles. - COX-2 source: LPS-stimulated murine peritoneal macrophages (1 μg/mL LPS, 16 h incubation). - Reaction system (200 μL): 50 mM Tris-HCl buffer (pH 8.0), 2 μM heme, 100 μM arachidonic acid (substrate), and serial dilutions of Nimesulide (R805) (0.01-100 μM). - Incubation: Mixtures were incubated at 37°C for 10 min or 30 min. The reaction was terminated by adding 20 μL of 1 M HCl. - Detection: Prostaglandin E2 (PGE2) concentration was measured using a radioimmunoassay (RIA) kit. Inhibition rate = (1 - sample PGE2/control PGE2) × 100%, and IC50 was calculated via nonlinear regression [1] |
| Cell Assay |
1. Primary endometrial carcinoma cell culture and angiogenic factor assay: - Cell isolation: Human endometrial carcinoma tissues were minced and digested with collagenase (0.1%) and hyaluronidase (0.05%) at 37°C for 2 h. Cells were filtered through a 70 μm strainer and cultured in RPMI 1640 medium + 10% fetal bovine serum (FBS). - Drug treatment: Cells were plated in 24-well plates (1×10⁵ cells/well) and treated with nimesulide (1 μM, 10 μM, 20 μM) for 48 h. - VEGF/bFGF detection: Culture supernatant was collected for ELISA (VEGF and bFGF concentration measurement). Total RNA was extracted from cells, reverse-transcribed to cDNA, and RT-PCR was performed using specific primers for VEGF, bFGF, and GAPDH (reference gene). - Cell viability assay: Cells were plated in 96-well plates (5×10³ cells/well), treated with nimesulide for 48 h, and MTT assay was performed to measure viability [3] |
| Animal Protocol |
1, 3 or 10 mg/kg; i.p. Rats: In the initial experiments, rats are pre-treated with intraperitoneal injections of 1, 3 or 10 mg/kg doses of Nimesulide, diluted in a 5% cremophor vehicle, or 2 mg/kg of indomethacin diluted in tris(hydroximetyl)-aminomethane-HCl (TRIS), pH 8.2, 30 min prior to an i.p. injection of LPS (50 μg/kg). Control animals receive the appropriate vehicle plus saline (1 mL/200 g, i.p.). The dose of 3 mg/kg of Nimesulide is chosen for the remaining experiments. In another set of experiments, rats are pretreated with an i.p. injection of Nimesulide (3 mg/kg) or indomethacin (2 mg/kg), diluted in the appropriate vehicles, 30 min prior to an i.c.v. injection (2 μL over 1 min) of IL-1β (3.12 ng), IL-6 (300 ng), TNF-α (250 ng), arachidonic acid (50 μg), MIP-1α (500 ng), PGE2 (250 ng), PGF2α (250 ng), CRF (2 μg) or ET-1 (1 pmol). Control animals receive the appropriate vehicles (1 mL/200 g, i.p.) and sterile saline (2 μL over 1 min, i.c.v.). All the drugs are injected between 10:00 and 11:00 AM to avoid circadian rhythm variations 1. Rat LPS-induced fever model: - Animals: Male Wistar rats (250-300 g), n=24, randomly divided into control group, LPS group, LPS + nimesulide 5 mg/kg group, LPS + nimesulide 10 mg/kg group (n=6/group). - Model induction: Rats were anesthetized with isoflurane, and body temperature was measured using a rectal probe (baseline). Fever was induced by intraperitoneal injection of LPS (100 μg/kg dissolved in normal saline). - Drug administration: Nimesulide (R805) was dissolved in 0.5% carboxymethyl cellulose (CMC-Na). One hour after LPS injection, drug groups received oral gavage (10 μL/g body weight); control and LPS groups received 0.5% CMC-Na. - Evaluation: Body temperature was measured every hour for 6 hours post-drug [2] 2. Rat yeast-induced fever model: - Animals: Male Wistar rats (250-300 g), n=18, randomly divided into control group, yeast group, yeast + nimesulide 10 mg/kg group, yeast + indomethacin 10 mg/kg group, yeast + indomethacin (5 mg/kg) + nimesulide (10 mg/kg) group (n=6/group except combination group, n=3). - Model induction: Fever was induced by subcutaneous injection of brewer’s yeast (20% w/v in normal saline, 10 mL/kg) into the dorsal neck. - Drug administration: Nimesulide or indomethacin was dissolved in 0.5% CMC-Na. Drugs were administered orally at the fever peak (18 hours post-yeast injection). - Evaluation: Body temperature was measured every hour for 6 hours post-drug [2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Rapidly absorbed following oral administration. Renal (50%), fecal (29%) Metabolism / Metabolites Hepatic. Extensive biotransformation, mainly to 4-hydroxynimesulide (which also appears to be biologically active). Biological Half-Life 1.8–4.7 hours |
| Toxicity/Toxicokinetics |
Hepatotoxicity Prospective studies show that up to 15% of patients taking NSAIDs experience at least transient serum aminotransferase elevations. A lower rate has been reported with nimesulide. These elevations are generally transient, mild and asymptomatic, and may resolve even with drug continuation. Marked aminotransferase elevations (>3 fold elevated) occur in Likelihood score: A (well established cause of clinically apparent liver injury). Protein Binding >97.5% |
| References |
[1]. Effect of nimesulide action time dependence on selectivity towards prostaglandin G/H synthase/cyclooxygenase activity. Arzneimittelforschung. 1995 Oct;45(10):1096-8. [2]. Nimesulide-induced antipyresis in rats involves both cyclooxygenase-dependent and independent mechanisms. Eur J Pharmacol. 2006 Aug 14;543(1-3):181-9. [3]. The effect of COX-2 inhibitor, nimesulide, on angiogenetic factors in primary endometrial carcinoma cell culture. Clin Exp Med. 2007 Mar;7(1):6-10. |
| Additional Infomation |
Nimesulide is an aromatic ether having phenyl and 2-methylsulfonamido-5-nitrophenyl as the two aryl groups. It has a role as a cyclooxygenase 2 inhibitor and a non-steroidal anti-inflammatory drug. It is a C-nitro compound, a sulfonamide and an aromatic ether. It is functionally related to a nitrobenzene. Nimesulide is a relatively COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. Its approved indications are the treatment of acute pain, the symptomatic treatment of osteoarthritis and primary dysmenorrhoea in adolescents and adults above 12 years old. Due to concerns about the risk of hepatotoxicity, nimesulide has been withdrawn from market in many countries. Nimesulide is a nonsteroidal antiinflammatory drug (NSAID) with relative specificity for COX-2 that is not available in the United States, but is used widely in other countries in the treatment of acute pain. Nimesulide has been linked to a low rate of transient serum enzyme elevations during therapy, but also to many instances of clinically apparent acute liver injury that can be severe and can result in acute liver failure, need for emergency liver transplantation and death. Nimesulide is a nonsteroidal arylsulfonamide with anti-inflammatory properties. Nimesulide inhibits the cyclooxygenase-mediated conversion of arachidonic acid to pro-inflammatory prostaglandins. Modestly selective for COX-2, this agent binds to the enzyme, thereby inactivating it. Nimesulide may inhibit some carcinogenic COX-2-related carcinogenic effects on xenobiotic metabolism, apoptosis, immune surveillance and angiogenesis (overexpressed COX-2 in tumor epithelial cells enhances production of vascular growth factors and the formation of capillary-like networks). (NCI04) Drug Indication For the treatment of acute pain, the symptomatic treatment of osteoarthritis and primary dysmenorrhoea in adolescents and adults above 12 years old. Mechanism of Action The therapeutic effects of Nimesulide are the result of its complete mode of action which targets a number of key mediators of the inflammatory process such as: COX-2 mediated prostaglandins, free radicals, proteolytic enzymes and histamine. Pharmacodynamics Food, gender and advanced age have negligible effects on nimesulide pharmacokinetics. 1. Nimesulide (R805) is a selective COX-2 inhibitor with time-dependent enhancement of COX-2 inhibition. Its high COX-2 selectivity (ratio >40) is attributed to stronger and more persistent binding to the COX-2 active site compared to COX-1 [1] 2. The antipyretic effect of nimesulide involves both COX-dependent and COX-independent mechanisms. The COX-dependent component is mediated by inhibiting PGE2 synthesis, while the COX-independent component may involve modulation of central thermoregulatory pathways (e.g., affecting cytokine signaling unrelated to COX) [2] 3. In endometrial carcinoma, nimesulide inhibits tumor angiogenesis by downregulating VEGF and bFGF expression, suggesting potential applications in cancer chemoprevention or adjuvant therapy for angiogenesis-dependent tumors [3] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.11 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 25.0 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: ≥ 2.5 mg/mL (8.11 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2435 mL | 16.2174 mL | 32.4349 mL | |
| 5 mM | 0.6487 mL | 3.2435 mL | 6.4870 mL | |
| 10 mM | 0.3243 mL | 1.6217 mL | 3.2435 mL |