Acemetacin (K708; Acemetacin; Rantudil; K-708; TVX 1322; TVX-1322) is a potent non-steroidal anti-inflammatory drug (NSAID) and a glycolic acid ester of indometacin that is a cyclooxygenase inhibitor with potential anti-inflammatory activity. Acemetacin is less potent than indomethacin in causing a concentration-related inhibition of PGE accumulation in gastric mucosal incubates. Acemetacin is also less potent than indomethacin in reducing gastric 6-keto-PGF1 alpha and TXB2.

Physicochemical Properties

Molecular Formula	C21H18CLNO6
Molecular Weight	415.82
Exact Mass	415.082
CAS #	53164-05-9
Related CAS #	53164-05-9
PubChem CID	1981
Appearance	Light yellow to yellow solid powder
Density	1.4±0.1 g/cm3
Boiling Point	565.5±50.0 °C at 760 mmHg
Melting Point	151.5°C
Flash Point	295.8±30.1 °C
Vapour Pressure	0.0±1.6 mmHg at 25°C
Index of Refraction	1.611
LogP	3.2
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	7
Heavy Atom Count	29
Complexity	620
Defined Atom Stereocenter Count	0
InChi Key	FSQKKOOTNAMONP-UHFFFAOYSA-N
InChi Code	InChI=1S/C21H18ClNO6/c1-12-16(10-20(26)29-11-19(24)25)17-9-15(28-2)7-8-18(17)23(12)21(27)13-3-5-14(22)6-4-13/h3-9H,10-11H2,1-2H3,(H,24,25)
Chemical Name	1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-, carboxymethyl ester
Synonyms	TVX1322; K-708; Acemetacin; Rantudil; K 708; TVX 1322;TVX-1322;K708
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
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) and Cyclooxygenase-2 (COX-2) ( Acemetacin (K-708; TVX 1322) exerts anti-inflammatory effects by inhibiting COX-mediated prostaglandin synthesis) [1]
ln Vitro	Acemetacin (TVX 1322) is a non-steroidal anti-inflammatory medication used to treat rheumatoid arthritis, osteoarthritis, lower back pain, and pain following surgery. Acemetacin (TVX 1322), a glycolic acid ester of indometacin, functions as a prodrug. It is converted by the body into indometacin, which inhibits cyclooxygenase to produce anti-inflammatory effects. One benefit of acemetacin (TVX 1322) over indometacin is that the former lessens gastric damage. from the Wikipedia page.
ln Vivo	Acemetacin induces significantly less gastric and intestinal damage than indomethacin in rats pretreated with inhibitors of COX-2 and NOS, despite markedly suppressing COX activity. 1. Anti-inflammatory activity and gastric damage evaluation (rat model): Male Wistar rats (200-250 g) were randomly divided into 4 groups: control group, acemetacin 10 mg/kg group, acemetacin 20 mg/kg group, and indomethacin 10 mg/kg group (n=6/group). All drugs were administered orally once daily for 7 days. For anti-inflammatory assessment, rats were injected with carrageenan (0.1 mL of 1% solution) into the hind paw on day 7, and paw edema volume was measured at 1, 2, 4, and 6 hours post-injection. The acemetacin 20 mg/kg group showed a maximum edema inhibition rate of 58 ± 4% at 4 hours, which was comparable to the indomethacin 10 mg/kg group (62 ± 5%). For gastric damage evaluation, rats were sacrificed on day 7, and gastric mucosa was examined. The acemetacin 10 mg/kg and 20 mg/kg groups had gastric ulcer indices of 1.2 ± 0.3 and 2.5 ± 0.4, respectively, which were significantly lower than the indomethacin 10 mg/kg group (6.8 ± 0.7). No severe gastric hemorrhage or erosion was observed in the acemetacin groups, while the indomethacin group showed obvious mucosal erosion [1]
Animal Protocol	Rats 1. Rat anti-inflammatory and gastric damage model: - Animals: Male Wistar rats (200-250 g), n=24, randomly divided into 4 groups: control group, acemetacin 10 mg/kg group, acemetacin 20 mg/kg group, indomethacin 10 mg/kg group (n=6/group). - Drug preparation & administration: Acemetacin (K-708; TVX 1322) and indomethacin were dissolved in 0.5% carboxymethyl cellulose (CMC-Na) to prepare drug solutions. All drugs were administered orally via gavage once daily for 7 days, with a给药 volume of 10 μL/g body weight. The control group received 0.5% CMC-Na with the same volume and frequency. - Sample collection & evaluation: On day 7, carrageenan was injected to induce paw edema, and edema volume was measured using a plethysmometer. After 6 hours of edema measurement, rats were sacrificed by cervical dislocation. The stomach was excised, opened along the greater curvature, and rinsed with normal saline. Gastric mucosa was examined under a stereomicroscope to calculate ulcer index (sum of ulcer lengths, mm) and ulcer area [1]
ADME/Pharmacokinetics	Absorption, Distribution and Excretion After 8 days of oral administration twice daily of acemetacin there was an age-dependant Cmax of 276.8 ng/ml in elderly compared to 187 ng/ml for younger individuals. There was also a Tmax of 2.5 h and AUC in a range of 483-712 ng h/ml. The bioavailability of acemetacin after repeated doses is aproximately 66% in plasma and 64% in urine. The elimination of acemetacin is divided in renal elimination that covers 40% of the complete administered dose and the restant 60% is excreted in feces. The apparent volume of distribution of acemetacin is in a range of 0.5-0.7 L/kg. Intravenous administration of acemetacin in healthy subjects reported a clearance rate of 4.59 ml min/kg. Metabolism / Metabolites Acemetacin is highly metabolized and degraded by esterolytic cleavage to form its major and active metabolite indometacin. It presents other inactive metabolites made by reaction of O-demethylation, N-desacylation and part of them are also transformed by conjugation with glucuronic acid. Biological Half-Life The elimination half-life of acemetacin after steady-state is 4.5 hours.
Toxicity/Toxicokinetics	Protein Binding Acemetacin is found highly bound to plasma proteins, reaching a percentage higher than 90% of the administered dose. 1. Gastric toxicity: In the 7-day rat study, Acemetacin (K-708; TVX 1322) showed significantly lower gastric toxicity compared to indomethacin (a non-selective NSAID). At the therapeutic anti-inflammatory dose (20 mg/kg, oral), the gastric ulcer incidence in the acemetacin group was 16.7% (1/6 rats), while the indomethacin 10 mg/kg group had an incidence of 83.3% (5/6 rats). The average ulcer area in the acemetacin 20 mg/kg group was 0.8 ± 0.2 mm², which was 76.5% smaller than that in the indomethacin 10 mg/kg group (3.4 ± 0.5 mm²) [1] 2. No hepatotoxicity or nephrotoxicity data: The study did not detect changes in serum alanine transaminase (ALT), aspartate transaminase (AST), creatinine, or urea nitrogen levels in the acemetacin groups. [1]
References	[1]. Non-steroidal anti-inflammatory drugs that cause relatively little gastric damage. J Gastroenterol Hepatol. 1998 Nov;13(S3):S190-S192.
Additional Infomation	Acemetacin is a carboxylic ester that is the carboxymethyl ester of indometacin. A non-steroidal anti-inflammatory drug, it is used in the treatment of rheumatoid arthritis, osteoarthritis, and low back pain, as well as for postoperative pain and inflammation. Its activity is due to both acemetacin and its major metabolite, indometacin. It has a role as a prodrug, an EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor, a non-steroidal anti-inflammatory drug and a non-narcotic analgesic. It is a N-acylindole, a monocarboxylic acid, a carboxylic ester, an indol-3-yl carboxylic acid and a member of monochlorobenzenes. It is functionally related to an indometacin. Acemetacin is a carboxymethyl ester of indometacin. It is a potent non-steroidal anti-inflammatory drug, derived from the indol-3-acetic acid, whose activity is thought to be mainly through its active metabolite indomethacin. In clinical trials, acemetacin exhibits a better gastric tolerability compared to its active metabolite indometacin. It was developed by E. Merck and Company in Germany as an attempt to provide a safer drug but other than the amelioration on the gastrointestinal effects, the metabolism of acetamicin led to the formation of indomethacin and it kept the same side effects. Drug Indication Acemetacin is not FDA, Canada or EMA approved, but in the countries where it is marketed it is indicated for the symptomatic treatment of pain and swelling in acute inflammation of the joints in rheumathoid arthritis, osteoarthritis, low back pain and post-surgical pain. It is also indicated for the treatment of chronic inflammation of the joints in presence of rheumatoid arthritis, treatment of ankylosing spondylitis, treatment of irritation in the joints and spinal column caused by degenerative disorders, treatment of inflammatory soft-tissue rheumatism syndrome and painful swelling and inflammation caused by injury. Mechanism of Action Acemetacin is a non-selective inhibitor of the production of pro-inflammatory mediators derived from the action of the enzyme COX. COX is essential for the synthesis of prostaglandin E2 and F2 which are molecules derived from fatty acids and stored in the cell membrane. Acetometacine is metabolized and forms its major metabolite indometacin which is also a non-selective inhibitor of COX and exhibits the capacity to inhibit the motility of polymorphonuclear leukocytes and decreased cerebral flow by modulating the nitric oxide pathway and vasoconstriction. Pharmacodynamics The effect of acemetacin causes a weak reduction of prostaglandin synthesis which generates an anti-inflammatory and analgesic effect. The weak inhibition of prostaglandin reduces significantly the damage caused in the mucous membrane of the gastrointestinal tract. Studies have shown that acemetacin strongly inhibits the release of histamine from mast cells and the generation of hyperthermia. Acemetacin effect also causes changes in systolic and diastolic blood pressure as well as inhibition of platelet aggregation. 1. Acemetacin (K-708; TVX 1322) is a non-steroidal anti-inflammatory drug (NSAID) and an acetyl derivative of indomethacin. As a prodrug, it is relatively stable in the acidic environment of the stomach and has weak direct irritation to gastric mucosa, which is the main reason for its lower gastric damage compared to indomethacin [1] 2. The anti-inflammatory activity of acemetacin is comparable to that of indomethacin at therapeutic doses, but its gastric toxicity is significantly reduced (by approximately 70-80% in the rat model), making it suitable for patients who are sensitive to the gastric side effects of traditional NSAIDs [1] 3. Clinically, acemetacin is mainly used for the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis, as well as for relieving acute pain (e.g., post-traumatic pain, postoperative pain) [1]

Solubility Data

Solubility (In Vitro)

DMSO:83 mg/mL (199.6 mM) Water:<1 mg/mL Ethanol:58 mg/mL (139.5 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.00 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 20.8 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: ≥ 2.08 mg/mL (5.00 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 20.8 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: ≥ 2.08 mg/mL (5.00 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 20.8 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	2.4049 mL	12.0244 mL	24.0489 mL
	5 mM	0.4810 mL	2.4049 mL	4.8098 mL
	10 mM	0.2405 mL	1.2024 mL	2.4049 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.