Camostat (100 μg/kg i.t.) induces a potent and prolonged attenuation of ENaC activity in the guinea pig trachea. Camostat mesilate (1-2 mg/g of diet) markedly attenuats an increase in hepatic plasmin and TGF-beta levels, HSC activation, and hepatic fibrosis without apparent systemic or local side effects in porcine serum–treated rats. Camostat mesilate (1 mg/g) prevents pancreatic atrophy and improves pancreatic exocrine function of rat chronic pancreatitis induced by DBTC. Camostat mesilate (1 mg/g) inhibits chronic inflammation and pancreatic fibrosis induced by DBTC. Camostat mesilate (1 mg/g) inhibits the development of pancreatic fibrosis and PSCs activation in the pancreas induced by DBTC. Camostat mesilate (1 mg/g) suppresses monocytes infiltration and inhibits MCP-1 expression both in serum and in pancreatic tissue. Camostat mesilate (100 mg/kg) significantly increases the body weight and pancreatic wet weight, and it significantly inhibits inflammatory changes and fibrosis of the pancreas through the suppression of gene expressions of PAP, p8, and cytokines in rat chronic pancreatitis.

Absorption, Distribution and Excretion
Following oral administration of 200 mg carmustine mesylate, the peak plasma concentration (Cmax) of the active metabolite was 87.1 ± 29.5 ng/mL, the time to peak concentration (Tmax) was 40 min, and the area under the curve (AUC) was 10,400 ± 1,400 ngmin/mL. 89.8-95.6% of carmustine mesylate is excreted in the urine, and 1.0-1.7% is excreted in the feces. The steady-state volume of distribution of carmustine mesylate is 0.34-1.31 L/kg. The clearance of carmustine mesylate is 4.5-7.3 mL/min/kg. Metabolism/Metabolite Carmustine mesylate is hydrolyzed by carboxylic acid esters to produce the active metabolite: 4-(4-guanidinobenzoyloxy)phenylacetate. The active metabolite is further hydrolyzed by aryl esterase to 4-guanidinobenzoic acid.

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Biological half-life
The half-life of carmosta mesylate is 3.8–4.7 hours.

Protein Binding
The binding rate of carmosstat mesylate to human serum proteins in vitro is 25.8-28.2%.

Camostat is a benzoic acid ester formed by the condensation of the carboxyl group of 4-guanidinobenzoic acid with the hydroxyl group of 2-(dimethylamino)-2-oxoethyl(4-hydroxyphenyl)acetic acid. It is a potent inhibitor of human transmembrane serine protease 2 (TMPRSS2), and its mesylate is currently being investigated for its efficacy in COVID-19 patients. Camostat possesses a variety of pharmacological activities, including anti-coronavirus, serine protease inhibitor, antifibrinolytic, anti-inflammatory, antiviral, antihypertensive, and antitumor activity. It is a tertiary amide, carboxylic acid ester, diester, guanidine compound, and benzoic acid ester. Its structure is related to 4-guanidinobenzoic acid. It is the conjugate base of carostat (1+). Camostat mesylate, also known as FOY-305, is a synthetic serine protease inhibitor. It was first reported in the literature in 1981, when studies focused on its inhibitory effect on mouse skin tumors. Carmosstat mesylate inhibits cholecystokinin, pro-inflammatory cytokines, and serine proteases, and has therefore been investigated for various indications, including the treatment of COVID-19. Carmosstat mesylate was first approved for marketing in Japan in January 2006. Carmosstat is a highly bioavailable, orally bioavailable synthetic serine protease inhibitor with anti-inflammatory, anti-fibrotic, and potential antiviral activities. Oral administration of carmosstat and its metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (FOY 251) inhibits the activity of various proteases, including trypsin, kallikrein, thrombin, and plasmin, as well as C1r and C1 esterases. Although the mechanism of action of carmosstat is not fully elucidated, activation of trypsinogen in the pancreas is known to be a triggering response for pancreatitis. Carmosstat blocks the activation of trypsinogen to trypsin and the inflammatory cascade it triggers. Carmostat can also inhibit the expression of cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β), as well as α-smooth muscle actin (α-SMA). This can alleviate pancreatic inflammation and fibrosis. Furthermore, carmostat may inhibit the activity of transmembrane serine protease 2 (TMPRSS2), a host cell serine protease that mediates the entry of influenza virus and coronavirus into cells, thereby inhibiting viral infection and replication.

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Drug Indications
In Japan, carmostat mesylate is approved for the treatment of chronic pancreatitis and drug-induced lung injury. It is currently being investigated as a potential treatment for COVID-19.

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Mechanism of Action
In rats, oral administration of carmostat mesylate increases pancreatic secretion and hypertrophy by increasing the release of cholecystokinin. Administration in rats also resulted in decreased levels of IL-1β, IL-6, TNF-α, TGF-β, and PSC. Similar activity was observed after human administration, reducing pain and inflammation and improving pancreatic function in patients with chronic pancreatitis. For SARS-CoV-2, carmostat mesylate inhibits the activity of the serine protease TMPRSS2, thereby preventing the viral spike protein from binding to ACE2 and entering cells.

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Pharmacodynamics
Carmostat mesylate is a protease inhibitor used to treat chronic pancreatitis. Because it is usually taken three times daily, its duration of action is short. Patients should be informed of the risks of allergic reactions, thrombocytopenia, liver dysfunction, and hyperkalemia.

C21H26N4O8S

494.519

398.159

59721-28-7

59721-29-8 (mesylate);59721-28-7;

2536

Typically exists as solid at room temperature

1.3±0.1 g/cm3

634.6±65.0 °C at 760 mmHg

194-198ºC

337.6±34.3 °C

0.0±1.9 mmHg at 25°C

1.597

1.29

2

6

9

29

602

0

O=C(OC1=CC=C(CC(OCC(N(C)C)=O)=O)C=C1)C2=CC=C(NC(N)=N)C=C2

XASIMHXSUQUHLV-UHFFFAOYSA-N

InChI=1S/C20H22N4O5/c1-24(2)17(25)12-28-18(26)11-13-3-9-16(10-4-13)29-19(27)14-5-7-15(8-6-14)23-20(21)22/h3-10H,11-12H2,1-2H3,(H4,21,22,23)

[4-[2-[2-(dimethylamino)-2-oxoethoxy]-2-oxoethyl]phenyl] 4-(diaminomethylideneamino)benzoate

FOY 305 Synonym

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)