Identification

Name
Gabexate
Accession Number
DB12831
Type
Small Molecule
Groups
Investigational
Description

Gabexate is a synthetic serine protease inhibitor which has been used as an anticoagulant. It also known to decrease production of inflammatory cytokines. Gabexate has been investigated for use in cancer, ischemia-reperfusion injury, and pancreatitis [4] [5] [6].

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Gabexate mesylateE3Q07L064956974-61-9DNTNDFLIKUKKOC-UHFFFAOYSA-N
Categories
UNII
4V7M9137X9
CAS number
39492-01-8
Weight
Average: 321.377
Monoisotopic: 321.168856233
Chemical Formula
C16H23N3O4
InChI Key
YKGYIDJEEQRWQH-UHFFFAOYSA-N
InChI
InChI=1S/C16H23N3O4/c1-2-22-15(21)12-7-9-13(10-8-12)23-14(20)6-4-3-5-11-19-16(17)18/h7-10H,2-6,11H2,1H3,(H4,17,18,19)
IUPAC Name
ethyl 4-[(6-carbamimidamidohexanoyl)oxy]benzoate
SMILES
CCOC(=O)C1=CC=C(OC(=O)CCCCCNC(N)=N)C=C1

Pharmacology

Indication

No approved indication.

Pharmacodynamics

Gabexate bind and inhibits serine proteases in the coagulation cascade to prevent blood clotting [3]. It also prevents proteolytic destruction of IkappaB resulting in suppression of the nuclear factor kappa-B signalling pathway [1]. Ultimately this decreases the production of inflammatory cytokines such as tumor necrosis factor alpha which are produced as a result of NFkappaB activation.

Mechanism of action

Gabexate inhibits kallikrein, plasmin, and thrombin by binding to their active sites [2] [3]. The inhibition of these components of the coagulation cascade ultimately prevents the formation of fibrin which must be present and polymerized to form a clot. Gabexate decreases the production of inflammatory cytokines by attenuating NFkappaB and c-Jun N-terminal kinase (JNK) pathway activity [1]. The exact mechanism for this is unknown but it is thought that gabexate prevents the proteolyytic destruction of IkappaB which deactivates NFkappaB and interferes with activator protein 1 binding to DNA.

TargetActionsOrganism
APlasma kallikrein
inhibitor
Human
AProthrombin
inhibitor
Human
APlasminogen
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

LD50 of 6480mg/kg observed in rats [MSDS].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Gabexate can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarin(R)-warfarin may increase the anticoagulant activities of Gabexate.
(S)-WarfarinGabexate may increase the anticoagulant activities of (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Gabexate can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Gabexate can be increased when used in combination with 18-methyl-19-nortestosterone.
4-hydroxycoumarin4-hydroxycoumarin may increase the anticoagulant activities of Gabexate.
4-HydroxytestosteroneThe therapeutic efficacy of Gabexate can be increased when used in combination with 4-Hydroxytestosterone.
5beta-dihydrotestosteroneThe therapeutic efficacy of Gabexate can be increased when used in combination with 5beta-dihydrotestosterone.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Gabexate.
AcenocoumarolAcenocoumarol may increase the anticoagulant activities of Gabexate.
Food Interactions
Not Available

References

General References
  1. Yuksel M, Okajima K, Uchiba M, Okabe H: Gabexate mesilate, a synthetic protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappaB and activator protein-1 in human monocytes. J Pharmacol Exp Ther. 2003 Apr;305(1):298-305. [PubMed:12649382]
  2. Menegatti E, Bolognesi M, Scalia S, Bortolotti F, Guarneri M, Ascenzi P: Gabexate mesylate inhibition of serine proteases: thermodynamic and computer-graphics analysis. J Pharm Sci. 1986 Dec;75(12):1171-4. [PubMed:3104578]
  3. Tamura Y, Hirado M, Okamura K, Minato Y, Fujii S: Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r-, and C1 esterase. Biochim Biophys Acta. 1977 Oct 13;484(2):417-22. [PubMed:143965]
  4. Brandi G, Tavolari S, De Rosa F, Di Girolamo S, Agostini V, Barbera MA, Frega G, Biasco G: Antitumoral efficacy of the protease inhibitor gabexate mesilate in colon cancer cells harbouring KRAS, BRAF and PIK3CA mutations. PLoS One. 2012;7(7):e41347. doi: 10.1371/journal.pone.0041347. Epub 2012 Jul 24. [PubMed:22911782]
  5. Xie LB, Zeng DY, Wang XD, Lin T, Li YP, Lu YP: Preconditioning with gabexate is superior to inosine for ameliorating acute renal ischemia-reperfusion injury in rats. Transplant Proc. 2014 Jan-Feb;46(1):40-5. doi: 10.1016/j.transproceed.2013.10.037. [PubMed:24507023]
  6. Kim SC, Yang HR: Clinical efficacy of gabexate mesilate for acute pancreatitis in children. Eur J Pediatr. 2013 Nov;172(11):1483-90. doi: 10.1007/s00431-013-2068-6. Epub 2013 Jun 29. [PubMed:23812506]
External Links
PubChem Compound
3447
PubChem Substance
347828997
ChemSpider
3329
BindingDB
50104435
ChEBI
93036
ChEMBL
CHEMBL87563
Wikipedia
Gabexate
MSDS
Download (79.7 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.109 mg/mLALOGPS
logP1.83ALOGPS
logP2.1ChemAxon
logS-3.5ALOGPS
pKa (Strongest Basic)12.13ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area114.5 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity96.7 m3·mol-1ChemAxon
Polarizability35.47 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00di-0119000000-c1086ad8b4cff4d62118

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzoic acid esters. These are ester derivatives of benzoic acid.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Benzoic acid esters
Alternative Parents
Phenol esters / Phenoxy compounds / Benzoyl derivatives / Fatty acid esters / Dicarboxylic acids and derivatives / Guanidines / Carboxylic acid esters / Carboximidamides / Organopnictogen compounds / Organic oxides
show 3 more
Substituents
Benzoate ester / Phenol ester / Phenoxy compound / Benzoyl / Fatty acid ester / Dicarboxylic acid or derivatives / Fatty acyl / Carboxylic acid ester / Guanidine / Carboxylic acid derivative
show 11 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen an...
Gene Name
KLKB1
Uniprot ID
P03952
Uniprot Name
Plasma kallikrein
Molecular Weight
71369.205 Da
References
  1. Tamura Y, Hirado M, Okamura K, Minato Y, Fujii S: Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r-, and C1 esterase. Biochim Biophys Acta. 1977 Oct 13;484(2):417-22. [PubMed:143965]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Thrombospondin receptor activity
Specific Function
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostas...
Gene Name
F2
Uniprot ID
P00734
Uniprot Name
Prothrombin
Molecular Weight
70036.295 Da
References
  1. Tamura Y, Hirado M, Okamura K, Minato Y, Fujii S: Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r-, and C1 esterase. Biochim Biophys Acta. 1977 Oct 13;484(2):417-22. [PubMed:143965]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type peptidase activity
Specific Function
Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In...
Gene Name
PLG
Uniprot ID
P00747
Uniprot Name
Plasminogen
Molecular Weight
90568.415 Da
References
  1. Tamura Y, Hirado M, Okamura K, Minato Y, Fujii S: Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r-, and C1 esterase. Biochim Biophys Acta. 1977 Oct 13;484(2):417-22. [PubMed:143965]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
Has activity against the synthetic substrates Boc-Phe-Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val-Pro-Arg-Mec. The single-chain form is more active than the two-chain form aga...
Gene Name
PRSS1
Uniprot ID
P07477
Uniprot Name
Trypsin-1
Molecular Weight
26557.88 Da
References
  1. Tamura Y, Hirado M, Okamura K, Minato Y, Fujii S: Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r-, and C1 esterase. Biochim Biophys Acta. 1977 Oct 13;484(2):417-22. [PubMed:143965]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activat...
Gene Name
C1S
Uniprot ID
P09871
Uniprot Name
Complement C1s subcomponent
Molecular Weight
76683.905 Da
References
  1. Tamura Y, Hirado M, Okamura K, Minato Y, Fujii S: Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r-, and C1 esterase. Biochim Biophys Acta. 1977 Oct 13;484(2):417-22. [PubMed:143965]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Serine-type peptidase activity
Specific Function
C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system.
Gene Name
C1R
Uniprot ID
P00736
Uniprot Name
Complement C1r subcomponent
Molecular Weight
80118.04 Da
References
  1. Tamura Y, Hirado M, Okamura K, Minato Y, Fujii S: Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r-, and C1 esterase. Biochim Biophys Acta. 1977 Oct 13;484(2):417-22. [PubMed:143965]

Drug created on October 20, 2016 18:33 / Updated on October 10, 2018 21:57