Description
Gabexate mesylate is a synthetic non-peptide protease inhibitor inhibiting plasmin, kallikrein, thrombin as well as trypsin, which attenuates pancreatic fibrosis. Reduces weight gain and improves metabolism in obese rodent models. In clinical use (in Japan) for pancreatitis. Inhibits influenza virus replication in human tracheal epithelial cells.4?Reduces infection of Calu-3 lung cells by SARS-CoV-2 (responsible for COVID-19) via inhibition of the serine protease TMPRSS2 required for viral spike protein priming.
Chemical Properties
Gabexate mesylate is supplied as a crystalline solid. A stock solution may be made by dissolving the gabexate (mesylate) in the solvent of choice. Gabexate (mesylate) is soluble in organic solvents such as DMSO and dimethyl formamide, which should be purged with an inert gas. The solubility of gabexate (mesylate) in these solvents is approximately 25 mg/ml.
Gabexate is a competitive inhibitor of serine proteases that inhibits human thrombin, urokinase, plasmin, and Factor Xa (Kis = 0.97, 1.3, 1.6, and 8.5 μM, respectively). It also inhibits bovine thrombin, Factor Xa, and trypsin, and porcine plasma kallikrein (Kis = 1.4, 2.1, 2.6, and 0.2 μM, respectively). In vitro, gabexate inhibits clotting activity of thrombin (IC50 = 10 μM).In vivo, it inhibits fibrin formation in rats when administered at a continuous infusion of 120 μmol/kg per hour. Gabexate inhibits LPS-stimulated TNF-α production from monocytes by inhibiting binding of NF-κB and activator protein 1 (AP-1) to target sites and inducing degradation of IκBα.
Originator
Gabexate Mesylate,Shangai Lansheng
Uses
Gabexate Mesylate is a serine protease inhibitor. Gabexate Mesylate inhibits trypsin, plasmin, plasma kallikrein and thrombin. Gabexate Mesylate inhibits lipopolysaccharide-induced tumor necrosis factor-α (TNF-α) production through nuclear factor-κB and activator protein-1 activation. Neuroresearch & Neuroprotective Product.
Uses
Pancreatitis;Serine protease inhibitor.
Gabexate Mesylate is a serine protease inhibitor with IC50 of 0.19 μM which is used therapeutically in the treatment of pancreatitis and disseminated intravascular coagulation.
Preparation
Guanidinocaproic acid p-tosyl salt and thionyl chloride were mixed together toreact at the room temperature. An endothermic reaction occurred and thecaproic acid gradually dissolved. Then the reaction mixture was left standingfor 1 to 2 h and was extracted with ether. The lower oily layer and the etherlayer were separated from each other and the lower layer was repeatedlywashed with ether. Then the oily substance (caproic acid chloride) was addedwith benzoic acid ethyl ester in tetrahydrofuran, and the mixture was stirred.After the mixture became a uniform solution, of pyridine were graduallyadded. An exothermic reaction occurred and an oily substance came to beseparated in the lower layer. After the completion of the reaction, the oilysubstance was washed with water and then recrystallized from hot water onceor twice. Thus 4-(6-guanidino-hexanoyloxy)-benzoic acid ethyl ester salt wasobtained as white crystals.
To obtained the base 4-(6-guanidino-hexanoyloxy)-benzoic acid ethyl esterthe 4-(6-guanidino-hexanoyloxy)-benzoic acid ethyl ester salt must be treatedby, for example, sodium hydroxide.
In practice it is usually used as gabexate Mesylate.
Definition
ChEBI: Gabexate methanesulfonate is a methanesulfonate salt, a member of guanidines and a benzoate ester.
Therapeutic Function
Enzyme inhibitor
Mechanism of action
Gabexate mesilate (FOY-007) is a protease inhibitor with a broad spectrum inhibiting not only trypsin and kallikrein, but also plasmin, thrombin,factor Xa, elastase, complement 1 (C1), esterase and phospholipase A2. Prophylactic application of FOY-007 or Camostat mesilate (FOY-305) showed some beneficial effect in CDEinduced pancreatitis, cerulein-induced panceratitis and sodium taurocholate-induced panceratitis. The therapeutic effect of FOY-007 in acute panceratitis has been ascribed to its inhibition of pancreatic enzyme activity, like trypsin, thus preventing autodigestion.
Clinical Use
Gabexate mesylate inhibits proteases and suppresses endothelial cell injury and may be used to treat DIC ascribed to various kinds of diseases.
Therapeutic Function: Enzyme inhibitor
References
[1] RODOLFO FEDERICO . Competitive Inhibition of Swine Kidney Copper Amine Oxidase by Drugs: Amiloride, Clonidine, and Gabexate Mesylate[J]. Biochemical and biophysical research communications, 1997, 240 1: Pages 150-152. DOI:
10.1006/bbrc.1997.7630.
[2] WAN-HEE YOON. Gabexate mesilate inhibits colon cancer growth, invasion, and metastasis by reducing matrix metalloproteinases and angiogenesis.[J]. Clinical Cancer Research, 2004, 10 13: 4517-4526. DOI:
10.1158/1078-0432.CCR-04-0084.
[3] JUNYA GIBO. Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity[J]. Laboratory Investigation, 2004, 85 1: 75-89. DOI:
10.1038/labinvest.3700203.
[4] KAMAL ALBARAZANJI. Intestinal serine protease inhibition increases FGF21 and improves metabolism in obese mice.[J]. American journal of physiology. Gastrointestinal and liver physiology, 2019, 316 5: G653-G667. DOI:
10.1152/ajpgi.00404.2018.
[5] MIKI UEDA. The serine protease inhibitor camostat mesilate attenuates the progression of chronic kidney disease through its antioxidant effects.[J]. Nephron, 2015, 129 3: 223-232. DOI:
10.1159/000375308.
[6] MUTSUO YAMAYA . The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells[J]. Pulmonary pharmacology & therapeutics, 2015, 33: Pages 66-74. DOI:
10.1016/j.pupt.2015.07.001.
[7] ALEXANDRA LINDSEY ZUNE DJOMKAM. Commentary: SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.[J]. ACS Applied Electronic Materials, 2020: 1448. DOI:
10.3389/fonc.2020.01448.
