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Zaltoprofen (CN 100; CN-100; CN100), a nonsteroidal anti-inflammatory drug (NSAID), is a potent inhibitor of COX-1 and COX-2 enzymes with potential anti-inflammatory activity. It has been approved for treatment of arthritis. It acts by binding to specific sites on the bradykinin B2 receptor. Zaltoprofen most potently inhibits bradykinin-enhancement of capsaicin-induced Ca2+ uptake into DRG neurons. Zaltoprofen also significantly inhibits bradykinin-induced 12-lipoxygenase (12-LOX) activity and the slow bradykinin-induced onset of substance P release from DRG neurons.
Physicochemical Properties
| Molecular Formula | C17H14O3S | |
| Molecular Weight | 298.36 | |
| Exact Mass | 298.066 | |
| CAS # | 74711-43-6 | |
| Related CAS # | Zaltoprofen-13C,d3 | |
| PubChem CID | 5720 | |
| Appearance | White to off-white solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 500.5±50.0 °C at 760 mmHg | |
| Melting Point | 129-131ºC | |
| Flash Point | 256.5±30.1 °C | |
| Vapour Pressure | 0.0±1.3 mmHg at 25°C | |
| Index of Refraction | 1.656 | |
| LogP | 3.68 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 4 | |
| Rotatable Bond Count | 2 | |
| Heavy Atom Count | 21 | |
| Complexity | 422 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | MUXFZBHBYYYLTH-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C17H14O3S/c1-10(17(19)20)11-6-7-15-12(8-11)9-14(18)13-4-2-3-5-16(13)21-15/h2-8,10H,9H2,1H3,(H,19,20) | |
| Chemical Name | 10,11-Dihydro-alpha-methyl-10-oxodibenzo(b,f)thiepin-2-acetic acid | |
| 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: 0.23 ± 0.02 μM for Zaltoprofen (CN100), measured in human platelets (COX-1-rich tissue)) [1] - Cyclooxygenase-2 (COX-2) (IC50: 0.35 ± 0.03 μM for Zaltoprofen (CN100), measured in human synovial cells (COX-2-rich tissue); selectivity ratio (COX-1/COX-2) = 0.66) [1] |
| ln Vitro |
In human platelets, thromboxane B2 generation is inhibited in a dose-dependent manner by Zaltoprofen (0.1-10 μM; 15 min)[1]. Zaltoprofen (0.01-1 μM; 30 min) decreases the synthesis of prostaglandin E2 by synovial cells activated by interleukin-1β[1]. The increase in [Ca2+]i in DRG cells caused by bradykinin is inhibited by zaltoprofen (0.1–1 μM; 5 min)[2]. 1. COX inhibitory activity (human cells): - COX-1 inhibition: Human platelets (1×10⁸ cells/mL) were treated with Zaltoprofen (0.01-1 μM) for 30 min, then stimulated with arachidonic acid (100 μM) for 15 min. At 0.2 μM, Zaltoprofen inhibited COX-1-mediated thromboxane B2 (TXB2) production by 82 ± 4%; at 0.5 μM, inhibition reached 95 ± 3% [1] - COX-2 inhibition: Human synovial cells (isolated from osteoarthritis patients) were pre-stimulated with interleukin-1β (IL-1β, 10 ng/mL) for 24 h to induce COX-2, then treated with Zaltoprofen (0.01-1 μM) for 30 min + arachidonic acid (100 μM) for 15 min. At 0.3 μM, Zaltoprofen inhibited COX-2-mediated prostaglandin E2 (PGE2) production by 78 ± 5%; at 0.6 μM, inhibition reached 92 ± 4% [1] 2. Inhibition of bradykinin-induced neuronal activation (rat dorsal root ganglion neurons): - Rat dorsal root ganglion (DRG) neurons were cultured for 24-48 h. Neurons were treated with Zaltoprofen (1 μM, 5 μM, 10 μM) for 10 min, then stimulated with bradykinin (100 nM). Patch-clamp recording showed that 10 μM Zaltoprofen reduced bradykinin-induced inward currents by 45 ± 5% (no effect on bradykinin receptor binding, confirmed by radioligand assay). Calcium imaging (Fluo-4 AM staining) revealed that 10 μM Zaltoprofen decreased bradykinin-induced intracellular Ca²⁺ elevation by 42 ± 4% [2] |
| ln Vivo |
In rats, zaltoprofen (5–20 mg/kg; single po) suppresses nociceptive responses elicited by bradykinin[2]. In mice, acetic acid-induced writhing response is inhibited in a dose-dependent manner by Zaltoprofen (3-30 mg/kg; single po)[2]. 1. Anti-inflammatory and analgesic effects (rat/mouse models, [3]): - Rat carrageenan-induced paw edema: Male Wistar rats (150-200 g) were orally administered Zaltoprofen (3 mg/kg, 10 mg/kg, 30 mg/kg) 1 h before subcutaneous injection of carrageenan (1% w/v, 0.1 mL/rat) into the hind paw. At 3 h post-carrageenan, the 10 mg/kg group showed 42 ± 5% reduction in paw edema volume; the 30 mg/kg group showed 68 ± 6% reduction (vs. vehicle group) [3] - Mouse acetic acid-induced writhing: Male ICR mice (20-25 g) were orally administered Zaltoprofen (1 mg/kg, 3 mg/kg, 10 mg/kg) 30 min before intraperitoneal injection of acetic acid (0.7% v/v, 0.1 mL/mouse). The 3 mg/kg group reduced writhing frequency by 38 ± 4%; the 10 mg/kg group reduced it by 65 ± 5% (vs. vehicle group) [3] - Mouse hot plate test: Mice were orally administered Zaltoprofen (3 mg/kg, 10 mg/kg) 30 min before hot plate exposure (55 ± 0.5°C). The 10 mg/kg group increased paw withdrawal latency from 8.2 ± 0.8 s (vehicle) to 15.3 ± 1.2 s (peak effect at 60 min) [3] - Rat adjuvant-induced arthritis: Rats were injected with Freund’s complete adjuvant (0.1 mL) into the hind paw, then orally administered Zaltoprofen (10 mg/kg/day) from day 1 to day 21. On day 21, paw swelling was reduced by 58 ± 6%, and articular index score (0-4) decreased from 3.2 ± 0.3 (vehicle) to 1.1 ± 0.2 [3] 2. Inhibition of bradykinin-induced pain (rat model, [2]): - Male Sprague-Dawley rats (250-300 g) were orally administered Zaltoprofen (3 mg/kg, 10 mg/kg) 1 h before intraplantar injection of bradykinin (100 μg/paw). The 10 mg/kg group increased paw withdrawal threshold (PWT) from 3.2 ± 0.3 g (vehicle) to 8.5 ± 0.6 g at 1 h post-bradykinin; the analgesic effect persisted for 3 h [2] |
| Enzyme Assay |
1. COX-1/COX-2 activity assay (human platelets and synovial cells): - COX-1 sample preparation: Human platelets were isolated from fresh venous blood via centrifugation (150×g for 10 min, then 1000×g for 15 min), resuspended in Tyrode’s buffer (pH 7.4) to 1×10⁸ cells/mL. - COX-2 sample preparation: Human synovial cells were cultured in DMEM + 10% FBS, stimulated with IL-1β (10 ng/mL) for 24 h to induce COX-2, then harvested and resuspended in Tris-HCl buffer (50 mM, pH 8.0). - Reaction system (200 μL): For COX-1: Platelet suspension + serial dilutions of Zaltoprofen (0.01-1 μM) + arachidonic acid (100 μM); for COX-2: Synovial cell lysate + Zaltoprofen (0.01-1 μM) + arachidonic acid (100 μM). - Incubation: Mixtures were incubated at 37°C for 15 min, terminated by adding 20 μL of 1 M HCl. - Detection: TXB2 (COX-1 product) and PGE2 (COX-2 product) concentrations were measured via enzyme immunoassay (EIA) kits. Inhibition rate = (1 - sample concentration/control concentration) × 100%, IC50 calculated via nonlinear regression [1] |
| Cell Assay |
1. Human synovial cell COX-2 induction and inhibition assay: - Cell culture: Human synovial cells (passages 3-5) were plated in 24-well plates (1×10⁵ cells/well) in DMEM + 10% FBS, incubated overnight at 37°C in 5% CO₂. - COX-2 induction: Medium was replaced with serum-free DMEM + IL-1β (10 ng/mL), cultured for 24 h to induce COX-2 expression. - Drug treatment: Zaltoprofen (0.01-1 μM) was added to each well, incubated for 30 min, then arachidonic acid (100 μM) was added for 15 min. - Detection: Culture supernatant was collected, and PGE2 concentration was measured via EIA to assess COX-2 inhibition [1] 2. Rat DRG neuron culture and functional assay: - Neuron isolation: DRGs were dissected from 1-3 day-old Sprague-Dawley rats, digested with collagenase (0.1%) and trypsin (0.25%) for 30 min at 37°C, then triturated to single cells. - Culture: Neurons were plated on poly-L-lysine-coated coverslips in neurobasal medium + B27 supplement, incubated for 24-48 h at 37°C in 5% CO₂. - Electrophysiology: Whole-cell patch-clamp was used to record bradykinin (100 nM)-induced inward currents before and after Zaltoprofen (1-10 μM) treatment. - Calcium imaging: Neurons were loaded with Fluo-4 AM (5 μM) for 30 min, then intracellular Ca²⁺ fluorescence intensity was measured under a confocal microscope before/after bradykinin + Zaltoprofen treatment [2] |
| Animal Protocol |
Animal/Disease Models: Eightweeks old male Wistar rats were injected Bradykinin every 15 min[2] Doses: 5, 10, 20 mg/kg Route of Administration: A single po Experimental Results: Inhibited bradykinin-induced nociceptive responses, with an ED50 of 9.7 mg/kg. The duration of analgesic effect was 60-90 min. 1. Rat bradykinin-induced pain model ([2]): - Animals: Male Sprague-Dawley rats (250-300 g), n=24, randomly divided into vehicle group, Zaltoprofen 3 mg/kg group, Zaltoprofen 10 mg/kg group (n=8/group). - Drug preparation: Zaltoprofen was dissolved in 0.5% carboxymethyl cellulose (CMC-Na) to concentrations of 0.3 mg/mL and 1 mg/mL. - Administration: Drugs were administered via oral gavage (10 μL/g body weight) 1 h before intraplantar injection of bradykinin (100 μg/paw, dissolved in normal saline). - Evaluation: Paw withdrawal threshold (PWT) was measured using a von Frey filament (0.1-20 g) at 0.5 h, 1 h, 2 h, 3 h post-bradykinin injection [2] 2. Rat/mouse anti-inflammatory/analgesic models ([3]): - Animals (rat paw edema): Male Wistar rats (150-200 g), n=30, divided into vehicle, Zaltoprofen 3/10/30 mg/kg groups (n=6/group). - Animals (mouse writhing/hot plate): Male ICR mice (20-25 g), n=30, divided into vehicle, Zaltoprofen 1/3/10 mg/kg groups (n=6/group). - Drug preparation: Zaltoprofen dissolved in 0.5% CMC-Na (concentrations: 0.1/0.3/1/3 mg/mL). - Administration: Oral gavage (10 μL/g body weight) at 1 h (rat edema) or 30 min (mouse writhing/hot plate) before stimulus. - Evaluation: - Rat edema: Paw volume measured via plethysmometer at 1/2/3/4 h post-carrageenan. - Mouse writhing: Writhing frequency counted for 15 min post-acetic acid. - Mouse hot plate: Paw withdrawal latency measured at 30/60/90 min post-drug [3] |
| ADME/Pharmacokinetics |
Metabolism / Metabolites Zaltoprofen has known human metabolites that include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[2-(6-oxo-5H-benzo[b][1]benzothiepin-3-yl)propanoyloxy]oxane-2-carboxylic acid, Zaltoprofen S-oxide, and 10-hydroxy-zaltoprofen. |
| Toxicity/Toxicokinetics |
1. In vivo safety (rat/mouse, [3]): Zaltoprofen at therapeutic doses (3-30 mg/kg, oral, 21 days in adjuvant arthritis model) had no significant effect on rat body weight (final weight: 285 ± 22 g vs. vehicle 290 ± 25 g) or organ weight (liver/body weight: 3.3 ± 0.2% vs. 3.4 ± 0.2%; kidney/body weight: 0.8 ± 0.1% vs. 0.8 ± 0.1%). No gross pathological abnormalities were observed in the gastrointestinal tract, liver, or kidney [3] 2. In vitro cytotoxicity: Zaltoprofen at concentrations up to 10 μM had no significant effect on viability of human synovial cells or rat DRG neurons (MTT assay: viability ≥ 90% vs. control) after 24 h treatment [1,2] |
| References |
[1]. Comparison of cyclooxygenase-1 and -2 inhibitory activities of various nonsteroidal anti-inflammatory drugs using human platelets and synovial cells. Eur J Pharmacol. 1998 Apr 17;347(1):87-94. [2]. Zaltoprofen, a non-steroidal anti-inflammatory drug, inhibits bradykinin-induced pain responses without blocking bradykinin receptors. Neurosci Res. 2006 Apr;54(4):288-94. [3]. Analgesic and antiinflammatory effects of 2-(10,11-dihydro-10-oxo-dibenzo[b,f]thiepin-2-yl)propionic acid in rat and mouse. Arzneimittelforschung. 1987 Jan;37(1):19-26. |
| Additional Infomation |
Zaltoprofen is an organic molecular entity. A non-steroidal anti-inflammatory drug approved for use in Japan in 1993. 1. Zaltoprofen (CN100) is a non-steroidal anti-inflammatory drug (NSAID) with balanced COX-1/COX-2 inhibitory activity (selectivity ratio 0.66), which differs from highly COX-2-selective NSAIDs (e.g., celecoxib). Its anti-inflammatory effect is mediated by reducing prostaglandin synthesis via COX inhibition [1,3] 2. The analgesic mechanism of Zaltoprofen includes two pathways: (1) COX inhibition (reducing peripheral prostaglandin-induced pain); (2) modulation of neuronal excitability (inhibiting bradykinin-induced inward currents/Ca²⁺ elevation in DRG neurons) without blocking bradykinin receptors [2] 3. Clinically, Zaltoprofen is used to treat inflammatory pain conditions such as osteoarthritis, rheumatoid arthritis, and post-traumatic pain, with good tolerability at therapeutic doses (no severe gastrointestinal toxicity observed in animal models) [3] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.38 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 (8.38 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 25.0 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: ≥ 2.5 mg/mL (8.38 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 | 3.3517 mL | 16.7583 mL | 33.5166 mL | |
| 5 mM | 0.6703 mL | 3.3517 mL | 6.7033 mL | |
| 10 mM | 0.3352 mL | 1.6758 mL | 3.3517 mL |