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enzymes (7) Show 7 proteins

Record Information

Version

5.0

Status

Expected but not Quantified

Creation Date

2012-09-06 15:16:51 UTC

Update Date

2022-03-07 02:51:54 UTC

HMDB ID

HMDB0015229

Secondary Accession Numbers

HMDB15229

Metabolite Identification

Common Name

Leflunomide

Description

Leflunomide is only found in individuals that have used or taken this drug. It is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Leflunomide was approved by FDA and in many other countries (e.g., Canada, Europe) in 1999. Leflunomide is a prodrug that is rapidly and almost completely metabolized following oral administration to its pharmacologically active metabolite, A77 1726. This metabolite is responsible for essentially all of the drug's activity in-vivo. The mechanism of action of leflunomide has not been fully determined, but appears to primarily involve regulation of autoimmune lymphocytes. It has been suggested that leflunomide exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interferences with cell cycle progression. In-vitro data indicates that leflunomide interferes with cell cycle progression by inhibiting dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine ribonucleotide uridine monophosphate (rUMP) synthesis) and has antiproliferative activity. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Other effects that result from reduced rUMP levels include interference with adhesion of activated lymphocytes to the synovial vascular endothelial cells, and increased synthesis of immunosuppressive cytokines such as transforming growth factor-β (TGF-β). Leflunomide is also a tyrosine kinase inhibitor. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells.

Structure

MOL 3D MOL SDF 3D SDF PDB 3D PDB SMILES InChI

1097
  Mrv0541 02231215142D          

 19 20  0  0  0  0            999 V2000
    2.9915    2.4910    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    4.6416    2.4910    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    3.8166    3.3160    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    2.6896   -3.3160    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    2.3876   -0.8090    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    3.8166   -0.8090    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    3.5146   -3.3160    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    3.8166    0.0160    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.8166    1.6660    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.1021   -2.0465    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.5310    0.4285    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.1021    0.4285    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.5310    1.2535    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.1021    1.2535    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.1021   -1.2215    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.4347   -2.5314    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.8166    2.4910    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.7695   -2.5314    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.6500   -2.2764    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  1 17  1  0  0  0  0
  2 17  1  0  0  0  0
  3 17  1  0  0  0  0
  4  7  1  0  0  0  0
  4 16  1  0  0  0  0
  5 15  2  0  0  0  0
  6  8  1  0  0  0  0
  6 15  1  0  0  0  0
  7 18  2  0  0  0  0
  8 11  2  0  0  0  0
  8 12  1  0  0  0  0
  9 13  2  0  0  0  0
  9 14  1  0  0  0  0
  9 17  1  0  0  0  0
 10 15  1  0  0  0  0
 10 16  2  0  0  0  0
 10 18  1  0  0  0  0
 11 13  1  0  0  0  0
 12 14  2  0  0  0  0
 16 19  1  0  0  0  0
M  END
> <DATABASE_ID>
HMDB0015229

> <DATABASE_NAME>
hmdb

> <SMILES>
CC1=C(C=NO1)C(=O)NC1=CC=C(C=C1)C(F)(F)F

> <INCHI_IDENTIFIER>
InChI=1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)

> <INCHI_KEY>
VHOGYURTWQBHIL-UHFFFAOYSA-N

> <FORMULA>
C12H9F3N2O2

> <MOLECULAR_WEIGHT>
270.2073

> <EXACT_MASS>
270.061612157

> <JCHEM_ACCEPTOR_COUNT>
2

> <JCHEM_AVERAGE_POLARIZABILITY>
23.107332045693916

> <JCHEM_BIOAVAILABILITY>
1

> <JCHEM_DONOR_COUNT>
1

> <JCHEM_FORMAL_CHARGE>
0

> <JCHEM_GHOSE_FILTER>
1

> <JCHEM_IUPAC>
5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide

> <ALOGPS_LOGP>
2.52

> <JCHEM_LOGP>
2.507085826

> <ALOGPS_LOGS>
-3.51

> <JCHEM_MDDR_LIKE_RULE>
0

> <JCHEM_NUMBER_OF_RINGS>
2

> <JCHEM_PHYSIOLOGICAL_CHARGE>
0

> <JCHEM_PKA_STRONGEST_ACIDIC>
10.412348150077646

> <JCHEM_PKA_STRONGEST_BASIC>
-0.44625320958288917

> <JCHEM_POLAR_SURFACE_AREA>
55.13

> <JCHEM_REFRACTIVITY>
64.15690000000001

> <JCHEM_ROTATABLE_BOND_COUNT>
3

> <JCHEM_RULE_OF_FIVE>
1

> <ALOGPS_SOLUBILITY>
8.44e-02 g/l

> <JCHEM_TRADITIONAL_IUPAC>
leflunomide

> <JCHEM_VEBER_RULE>
0

$$$$

HEADER    PROTEIN                                 23-FEB-12   NONE
TITLE     NULL                                                        
COMPND    MOLECULE: 1097                                              
SOURCE    NULL                                                        
KEYWDS    NULL                                                        
EXPDTA    NULL                                                        
AUTHOR    Marvin                                                      
REVDAT   1   23-FEB-12         0                                  
HETATM    1  F   UNK     0       5.584   4.650   0.000  0.00  0.00           F+0
HETATM    2  F   UNK     0       8.664   4.650   0.000  0.00  0.00           F+0
HETATM    3  F   UNK     0       7.124   6.190   0.000  0.00  0.00           F+0
HETATM    4  O   UNK     0       5.021  -6.190   0.000  0.00  0.00           O+0
HETATM    5  O   UNK     0       4.457  -1.510   0.000  0.00  0.00           O+0
HETATM    6  N   UNK     0       7.124  -1.510   0.000  0.00  0.00           N+0
HETATM    7  N   UNK     0       6.561  -6.190   0.000  0.00  0.00           N+0
HETATM    8  C   UNK     0       7.124   0.030   0.000  0.00  0.00           C+0
HETATM    9  C   UNK     0       7.124   3.110   0.000  0.00  0.00           C+0
HETATM   10  C   UNK     0       5.791  -3.820   0.000  0.00  0.00           C+0
HETATM   11  C   UNK     0       8.458   0.800   0.000  0.00  0.00           C+0
HETATM   12  C   UNK     0       5.791   0.800   0.000  0.00  0.00           C+0
HETATM   13  C   UNK     0       8.458   2.340   0.000  0.00  0.00           C+0
HETATM   14  C   UNK     0       5.791   2.340   0.000  0.00  0.00           C+0
HETATM   15  C   UNK     0       5.791  -2.280   0.000  0.00  0.00           C+0
HETATM   16  C   UNK     0       4.545  -4.725   0.000  0.00  0.00           C+0
HETATM   17  C   UNK     0       7.124   4.650   0.000  0.00  0.00           C+0
HETATM   18  C   UNK     0       7.036  -4.725   0.000  0.00  0.00           C+0
HETATM   19  C   UNK     0       3.080  -4.249   0.000  0.00  0.00           C+0
CONECT    1   17                                                            
CONECT    2   17                                                            
CONECT    3   17                                                            
CONECT    4    7   16                                                       
CONECT    5   15                                                            
CONECT    6    8   15                                                       
CONECT    7    4   18                                                       
CONECT    8    6   11   12                                                  
CONECT    9   13   14   17                                                  
CONECT   10   15   16   18                                                  
CONECT   11    8   13                                                       
CONECT   12    8   14                                                       
CONECT   13    9   11                                                       
CONECT   14    9   12                                                       
CONECT   15    5    6   10                                                  
CONECT   16    4   10   19                                                  
CONECT   17    1    2    3    9                                             
CONECT   18    7   10                                                       
CONECT   19   16                                                            
MASTER        0    0    0    0    0    0    0    0   19    0   40    0
END

COMPND    HMDB0015229
HETATM    1  C1  UNL     1       4.179   1.112  -0.629  1.00  0.00           C  
HETATM    2  C2  UNL     1       3.893  -0.104   0.188  1.00  0.00           C  
HETATM    3  O1  UNL     1       4.926  -0.860   0.618  1.00  0.00           O  
HETATM    4  N1  UNL     1       4.506  -1.852   1.309  1.00  0.00           N  
HETATM    5  C3  UNL     1       3.172  -1.806   1.367  1.00  0.00           C  
HETATM    6  C4  UNL     1       2.768  -0.652   0.632  1.00  0.00           C  
HETATM    7  C5  UNL     1       1.373  -0.388   0.478  1.00  0.00           C  
HETATM    8  O2  UNL     1       0.582  -0.407   1.512  1.00  0.00           O  
HETATM    9  N2  UNL     1       0.640  -0.083  -0.731  1.00  0.00           N  
HETATM   10  C6  UNL     1      -0.788   0.050  -0.575  1.00  0.00           C  
HETATM   11  C7  UNL     1      -1.320   1.227  -0.187  1.00  0.00           C  
HETATM   12  C8  UNL     1      -2.692   1.344  -0.006  1.00  0.00           C  
HETATM   13  C9  UNL     1      -3.506   0.261  -0.219  1.00  0.00           C  
HETATM   14  C10 UNL     1      -4.976   0.376  -0.033  1.00  0.00           C  
HETATM   15  F1  UNL     1      -5.255   0.879   1.207  1.00  0.00           F  
HETATM   16  F2  UNL     1      -5.570  -0.886  -0.244  1.00  0.00           F  
HETATM   17  F3  UNL     1      -5.428   1.276  -0.993  1.00  0.00           F  
HETATM   18  C11 UNL     1      -2.945  -0.946  -0.619  1.00  0.00           C  
HETATM   19  C12 UNL     1      -1.605  -1.067  -0.802  1.00  0.00           C  
HETATM   20  H1  UNL     1       3.307   1.736  -0.743  1.00  0.00           H  
HETATM   21  H2  UNL     1       4.630   0.883  -1.624  1.00  0.00           H  
HETATM   22  H3  UNL     1       4.981   1.687  -0.058  1.00  0.00           H  
HETATM   23  H4  UNL     1       2.463  -2.454   1.849  1.00  0.00           H  
HETATM   24  H5  UNL     1       1.097   0.043  -1.618  1.00  0.00           H  
HETATM   25  H6  UNL     1      -0.632   2.084  -0.034  1.00  0.00           H  
HETATM   26  H7  UNL     1      -3.049   2.315   0.340  1.00  0.00           H  
HETATM   27  H8  UNL     1      -3.645  -1.767  -0.745  1.00  0.00           H  
HETATM   28  H9  UNL     1      -1.107  -1.999  -1.116  1.00  0.00           H  
CONECT    1    2   20   21   22
CONECT    2    3    6    6
CONECT    3    4
CONECT    4    5    5
CONECT    5    6   23
CONECT    6    7
CONECT    7    8    8    9
CONECT    9   10   24
CONECT   10   11   11   19
CONECT   11   12   25
CONECT   12   13   13   26
CONECT   13   14   18
CONECT   14   15   16   17
CONECT   18   19   19   27
CONECT   19   28
END

View in JSmol View Stereo Labels

Synonyms

Value	Source
5-Methyl-N-(4-(trifluoromethyl)phenyl)-4-isoxazolecarboxamide	ChEBI
5-Methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide	ChEBI
alpha,alpha,alpha-Trifluoro-5-methyl-4-isoxazolecarboxy-p-toluidide	ChEBI
Arava	ChEBI
Leflunomida	ChEBI
Leflunomidum	ChEBI
5-Methylisoxazole-4-carboxylate (4-trifluoromethyl)anilide	Generator
a,a,a-Trifluoro-5-methyl-4-isoxazolecarboxy-p-toluidide	Generator
Α,α,α-trifluoro-5-methyl-4-isoxazolecarboxy-p-toluidide	Generator
Aventis behring brand OF leflunomide	HMDB
Aventis brand OF leflunomide	HMDB
HWA 486	HMDB
HWA-486	HMDB
Aventis pharma brand OF leflunomide	HMDB
Hoechst brand OF leflunomide	HMDB
N-(4-Trifluoromethyphenyl)-5-methylisoxazole-4-carboxamide	HMDB

Chemical Formula

C₁₂H₉F₃N₂O₂

Average Molecular Weight

270.2073

Monoisotopic Molecular Weight

270.061612157

IUPAC Name

5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide

Traditional Name

leflunomide

CAS Registry Number

75706-12-6

SMILES

CC1=C(C=NO1)C(=O)NC1=CC=C(C=C1)C(F)(F)F

InChI Identifier

InChI=1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)

InChI Key

VHOGYURTWQBHIL-UHFFFAOYSA-N

Chemical Taxonomy

Description

Belongs to the class of organic compounds known as aromatic anilides. These are aromatic compounds containing an anilide group in which the carboxamide group is substituted with an aromatic group. They have the general structure RNC(=O)R', where R= benzene, and R = aryl group.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Anilides

Direct Parent

Aromatic anilides

Alternative Parents

Substituents

Aromatic anilide
Trifluoromethylbenzene
Azole
Isoxazole
Heteroaromatic compound
Carboxamide group
Secondary carboxylic acid amide
Carboxylic acid derivative
Organoheterocyclic compound
Azacycle
Oxacycle
Organic oxide
Organooxygen compound
Organonitrogen compound
Organofluoride
Organohalogen compound
Organopnictogen compound
Alkyl fluoride
Organic oxygen compound
Alkyl halide
Organic nitrogen compound
Hydrocarbon derivative
Aromatic heteromonocyclic compound

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

monocarboxylic acid amide (CHEBI:6402 )
isoxazoles (CHEBI:6402 )
(trifluoromethyl)benzenes (CHEBI:6402 )

Ontology

Not Available

Urine (PMID: 21059682)

Non-excretory biofluid

Biofluid or Excreta

Blood (PMID: 21059682)

Cellular substructure

Cytoplasm (HMDB: HMDB0015229)
Membrane (HMDB: HMDB0015229)

Process

Not Available

Role

Not Available

Physical Properties

State

Solid

Experimental Molecular Properties

Property	Value	Reference
Melting Point	165 - 166 °C	Not Available
Boiling Point	Not Available	Not Available
Water Solubility	0.084 g/L	Not Available
LogP	2.8	Not Available

Experimental Chromatographic Properties

Not Available

Predicted Molecular Properties

Property	Value	Source
Water Solubility	0.084 g/L	ALOGPS
logP	2.52	ALOGPS
logP	2.51	ChemAxon
logS	-3.5	ALOGPS
pKa (Strongest Acidic)	10.41	ChemAxon
pKa (Strongest Basic)	-0.45	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	55.13 Å²	ChemAxon
Rotatable Bond Count	3	ChemAxon
Refractivity	64.16 m³·mol⁻¹	ChemAxon
Polarizability	23.11 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	Yes	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted Chromatographic Properties

Predicted Collision Cross Sections

Predictor	Adduct Type	CCS Value (Å²)	Reference
DeepCCS	[M+H]+	161.838	30932474
DeepCCS	[M-H]-	159.48	30932474
DeepCCS	[M-2H]-	193.015	30932474
DeepCCS	[M+Na]+	168.242	30932474
AllCCS	[M+H]+	158.5	32859911
AllCCS	[M+H-H2O]+	154.7	32859911
AllCCS	[M+NH4]+	161.9	32859911
AllCCS	[M+Na]+	162.9	32859911
AllCCS	[M-H]-	156.9	32859911
AllCCS	[M+Na-2H]-	156.4	32859911
AllCCS	[M+HCOO]-	155.9	32859911

Predicted Kovats Retention Indices

Underivatized

Metabolite	SMILES	Kovats RI Value	Column Type	Reference
Leflunomide	CC1=C(C=NO1)C(=O)NC1=CC=C(C=C1)C(F)(F)F	2401.1	Standard polar	33892256
Leflunomide	CC1=C(C=NO1)C(=O)NC1=CC=C(C=C1)C(F)(F)F	1909.1	Standard non polar	33892256
Leflunomide	CC1=C(C=NO1)C(=O)NC1=CC=C(C=C1)C(F)(F)F	1930.1	Semi standard non polar	33892256

Derivatized

Derivative Name / Structure	SMILES	Kovats RI Value	Column Type	Reference
Leflunomide,1TMS,isomer #1	CC1=C(C(=O)N(C2=CC=C(C(F)(F)F)C=C2)[Si](C)(C)C)C=NO1	1889.4	Semi standard non polar	33892256
Leflunomide,1TMS,isomer #1	CC1=C(C(=O)N(C2=CC=C(C(F)(F)F)C=C2)[Si](C)(C)C)C=NO1	1966.8	Standard non polar	33892256
Leflunomide,1TMS,isomer #1	CC1=C(C(=O)N(C2=CC=C(C(F)(F)F)C=C2)[Si](C)(C)C)C=NO1	2161.1	Standard polar	33892256
Leflunomide,1TBDMS,isomer #1	CC1=C(C(=O)N(C2=CC=C(C(F)(F)F)C=C2)[Si](C)(C)C(C)(C)C)C=NO1	2134.5	Semi standard non polar	33892256
Leflunomide,1TBDMS,isomer #1	CC1=C(C(=O)N(C2=CC=C(C(F)(F)F)C=C2)[Si](C)(C)C(C)(C)C)C=NO1	2138.9	Standard non polar	33892256
Leflunomide,1TBDMS,isomer #1	CC1=C(C(=O)N(C2=CC=C(C(F)(F)F)C=C2)[Si](C)(C)C(C)(C)C)C=NO1	2285.4	Standard polar	33892256

Spectra

GC-MS Spectra

Spectrum Type	Description	Splash Key	Deposition Date	Source	View
Predicted GC-MS	Predicted GC-MS Spectrum - Leflunomide GC-MS (Non-derivatized) - 70eV, Positive	splash10-03di-7970000000-03045269425a638f328c	2017-09-01	Wishart Lab	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - Leflunomide GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	Wishart Lab	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - Leflunomide GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	Wishart Lab	View Spectrum

MS/MS Spectra

Spectrum Type	Description	Splash Key	Deposition Date	Source	View
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide LC-ESI-qTof , Positive-QTOF	splash10-00di-0390000000-1ac4065d1ef245442a16	2017-09-14	HMDB team, MONA	View Spectrum
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide LC-ESI-qTof , Positive-QTOF	splash10-05gi-3920000000-db0dc9413f5ca5cb69e3	2017-09-14	HMDB team, MONA	View Spectrum
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide , positive-QTOF	splash10-00di-0390000000-1ac4065d1ef245442a16	2017-09-14	HMDB team, MONA	View Spectrum
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide , positive-QTOF	splash10-03di-2920000000-819d0674f452a60be1a4	2017-09-14	HMDB team, MONA	View Spectrum
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide 90V, Negative-QTOF	splash10-00lr-9200000000-414a713461b4237c6e71	2021-09-20	HMDB team, MONA	View Spectrum
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide 75V, Negative-QTOF	splash10-001i-9200000000-e21878adb74f0a5190bc	2021-09-20	HMDB team, MONA	View Spectrum
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide 15V, Negative-QTOF	splash10-00lr-9050000000-6c169fcd04bf0a4c16a8	2021-09-20	HMDB team, MONA	View Spectrum
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide 30V, Negative-QTOF	splash10-001i-9110000000-459c33159bb27094ea91	2021-09-20	HMDB team, MONA	View Spectrum
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide 60V, Negative-QTOF	splash10-001i-9200000000-a48fe3379802d9cfce95	2021-09-20	HMDB team, MONA	View Spectrum
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide 45V, Negative-QTOF	splash10-001i-9200000000-19d3236cea84dc0f5ff1	2021-09-20	HMDB team, MONA	View Spectrum
Experimental LC-MS/MS	LC-MS/MS Spectrum - Leflunomide 60V, Positive-QTOF	splash10-001i-9200000000-0ef7ffe353ea10020f8d	2021-09-20	HMDB team, MONA	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 10V, Positive-QTOF	splash10-00di-0390000000-e07a793be0a4de994083	2016-08-01	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 20V, Positive-QTOF	splash10-03di-1930000000-dbdbb3e67b067703099d	2016-08-01	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 40V, Positive-QTOF	splash10-03di-7900000000-24b45cc5af1bf1c20902	2016-08-01	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 10V, Negative-QTOF	splash10-014i-3090000000-039b17df86bfcf213d45	2016-08-03	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 20V, Negative-QTOF	splash10-001i-9010000000-95fb3f6c8f86b32a3a33	2016-08-03	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 40V, Negative-QTOF	splash10-01q9-9100000000-0bee5f2dec9154ee9333	2016-08-03	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 10V, Positive-QTOF	splash10-00di-1190000000-320ce8ab21656bf61a98	2021-10-11	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 20V, Positive-QTOF	splash10-00di-2490000000-e7bd4a27fe1066098f17	2021-10-11	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 40V, Positive-QTOF	splash10-01ox-9320000000-01ed6f4bd00aeceec987	2021-10-11	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 10V, Negative-QTOF	splash10-0159-5090000000-2d9438c678553c6a4277	2021-10-11	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 20V, Negative-QTOF	splash10-03di-2920000000-70daf72ac22ca58c8b59	2021-10-11	Wishart Lab	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - Leflunomide 40V, Negative-QTOF	splash10-03di-0900000000-f53ae2f06f61c346c9e3	2021-10-11	Wishart Lab	View Spectrum

Biological Properties

Cellular Locations

Cytoplasm
Membrane

Biospecimen Locations

Blood
Urine

Tissue Locations

Not Available

Pathways

Not Available

Name	SMPDB/PathBank	KEGG

Normal Concentrations

Biospecimen	Status	Value	Age	Sex	Condition	Reference	Details
Blood	Expected but not Quantified	Not Quantified	Not Available	Not Available	Taking drug identified by DrugBank entry DB01097	21059682	details
Urine	Expected but not Quantified	Not Quantified	Not Available	Not Available	Taking drug identified by DrugBank entry DB01097	21059682	details

Abnormal Concentrations

Not Available

Associated Disorders and Diseases

Disease References

None

Associated OMIM IDs

None

External Links

DrugBank ID

DB01097

Phenol Explorer Compound ID

Not Available

FooDB ID

Not Available

KNApSAcK ID

Not Available

Chemspider ID

3762

KEGG Compound ID

C07905

BioCyc ID

Not Available

BiGG ID

Not Available

Wikipedia Link

Leflunomide

METLIN ID

Not Available

PubChem Compound

3899

PDB ID

Not Available

ChEBI ID

6402

Food Biomarker Ontology

Not Available

VMH ID

Not Available

MarkerDB ID

Not Available

Good Scents ID

Not Available

References

Synthesis Reference

Not Available

Material Safety Data Sheet (MSDS)

Not Available

General References

Goldenberg MM: Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. Clin Ther. 1999 Nov;21(11):1837-52; discussion 1821. [PubMed:10890256 ]
Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. [PubMed:15189743 ]
Sanders S, Harisdangkul V: Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J Med Sci. 2002 Apr;323(4):190-3. [PubMed:12003373 ]
Breedveld FC, Dayer JM: Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000 Nov;59(11):841-9. [PubMed:11053058 ]
Herrmann ML, Schleyerbach R, Kirschbaum BJ: Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology. 2000 May;47(2-3):273-89. [PubMed:10878294 ]
Schattenkirchner M: The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review. Immunopharmacology. 2000 May;47(2-3):291-8. [PubMed:10878295 ]
Fox RI: Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. [PubMed:9666414 ]

Enzymes

Enzyme Details

1. Dihydroorotate dehydrogenase (quinone), mitochondrial

General function:: Involved in catalytic activity
Specific function:: Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Gene Name:: DHODH
Uniprot ID:: Q02127
Molecular weight:: 42866.93

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Goldenberg MM: Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. Clin Ther. 1999 Nov;21(11):1837-52; discussion 1821. [PubMed:10890256 ]
Prakash A, Jarvis B: Leflunomide: a review of its use in active rheumatoid arthritis. Drugs. 1999 Dec;58(6):1137-64. [PubMed:10651393 ]
Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. [PubMed:15189743 ]
Wozel G, Pfeiffer C: [Leflunomide--a new drug for pharmacological immunomodulation]. Hautarzt. 2002 May;53(5):309-15. [PubMed:12063741 ]
Sanders S, Harisdangkul V: Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J Med Sci. 2002 Apr;323(4):190-3. [PubMed:12003373 ]
Breedveld FC, Dayer JM: Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000 Nov;59(11):841-9. [PubMed:11053058 ]
Reitzik M, Lownie JF: Familial polyostotic fibrous dysplasia. Oral Surg Oral Med Oral Pathol. 1975 Dec;40(6):769-74. [PubMed:1060033 ]
Herrmann ML, Schleyerbach R, Kirschbaum BJ: Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology. 2000 May;47(2-3):273-89. [PubMed:10878294 ]
Schattenkirchner M: The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review. Immunopharmacology. 2000 May;47(2-3):291-8. [PubMed:10878295 ]
Fox RI: Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. [PubMed:9666414 ]
Fukushima R, Kanamori S, Hirashiba M, Hishikawa A, Muranaka RI, Kaneto M, Nakamura K, Kato I: Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice. Reprod Toxicol. 2007 Nov-Dec;24(3-4):310-6. Epub 2007 May 18. [PubMed:17604599 ]

Enzyme Details

2. Arachidonate 5-lipoxygenase

General function:: Involved in metal ion binding
Specific function:: Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes.
Gene Name:: ALOX5
Uniprot ID:: P09917
Molecular weight:: 77982.595

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Enzyme Details

3. Cytochrome P450 2C9

General function:: Involved in monooxygenase activity
Specific function:: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
Gene Name:: CYP2C9
Uniprot ID:: P11712
Molecular weight:: 55627.365

References

Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

Enzyme Details

4. Protein-tyrosine kinase 2-beta

General function:: Involved in binding
Specific function:: Involved in calcium induced regulation of ion channel and activation of the map kinase signaling pathway. May represent an important signaling intermediate between neuropeptide activated receptors or neurotransmitters that increase calcium flux and the downstream signals that regulate neuronal activity. Interacts with the SH2 domain of Grb2. May phosphorylate the voltage-gated potassium channel protein Kv1.2. Its activation is highly correlated with the stimulation of c-Jun N-terminal kinase activity. Involved in osmotic stress-dependent SNCA 'Tyr-125' phosphorylation
Gene Name:: PTK2B
Uniprot ID:: Q14289
Molecular weight:: 115873.6

References

Pytel D, Sliwinski T, Poplawski T, Ferriola D, Majsterek I: Tyrosine kinase blockers: new hope for successful cancer therapy. Anticancer Agents Med Chem. 2009 Jan;9(1):66-76. [PubMed:19149483 ]
Fukushima R, Kanamori S, Hirashiba M, Hishikawa A, Muranaka RI, Kaneto M, Nakamura K, Kato I: Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice. Reprod Toxicol. 2007 Nov-Dec;24(3-4):310-6. Epub 2007 May 18. [PubMed:17604599 ]
Steeghs N, Nortier JW, Gelderblom H: Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. Ann Surg Oncol. 2007 Feb;14(2):942-53. Epub 2006 Nov 14. [PubMed:17103252 ]

Enzyme Details

5. Cytochrome P450 1A2

General function:: Involved in monooxygenase activity
Specific function:: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen. Participates in the bioactivation of carcinogenic aromatic and heterocyclic amines. Catalizes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin.
Gene Name:: CYP1A2
Uniprot ID:: P05177
Molecular weight:: 58406.915

References

Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. [PubMed:19754423 ]
Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014 ]

Enzyme Details

6. Cytochrome P450 2C8

General function:: Involved in monooxygenase activity
Specific function:: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti-cancer drug paclitaxel (taxol).
Gene Name:: CYP2C8
Uniprot ID:: P10632
Molecular weight:: 55824.275

References

Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

Enzyme Details

7. Aryl hydrocarbon receptor

General function:: Involved in transcription regulator activity
Specific function:: Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues
Gene Name:: AHR
Uniprot ID:: P35869
Molecular weight:: 96146.7

References

O'Donnell EF, Saili KS, Koch DC, Kopparapu PR, Farrer D, Bisson WH, Mathew LK, Sengupta S, Kerkvliet NI, Tanguay RL, Kolluri SK: The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. PLoS One. 2010 Oct 1;5(10). pii: e13128. doi: 10.1371/journal.pone.0013128. [PubMed:20957046 ]
Hu W, Sorrentino C, Denison MS, Kolaja K, Fielden MR: Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol Pharmacol. 2007 Jun;71(6):1475-86. Epub 2007 Feb 27. [PubMed:17327465 ]

Showing metabocard for Leflunomide (HMDB0015229)

MOL for HMDB0015229 (Leflunomide)

3D MOL for HMDB0015229 (Leflunomide)

3D SDF for HMDB0015229 (Leflunomide)

3D-SDF for HMDB0015229 (Leflunomide)

PDB for HMDB0015229 (Leflunomide)

3D PDB for HMDB0015229 (Leflunomide)

SMILES for HMDB0015229 (Leflunomide)

INCHI for HMDB0015229 (Leflunomide)

Structure for HMDB0015229 (Leflunomide)

3D Structure for HMDB0015229 (Leflunomide)

Predicted Collision Cross Sections

Predicted Kovats Retention Indices

Underivatized

Derivatized

GC-MS Spectra

MS/MS Spectra

Enzymes

References

References

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