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Identification
NameLicofelone
Accession NumberDB04725
TypeSmall Molecule
GroupsInvestigational
DescriptionDeveloped by the German pharmaceutical company, Merckle GmbH, together with EuroAlliance partners Alfa Wassermann and Lacer, licofelone (ML3000) is a dual COX/LOX inhibitor and the first member of this new class of analgesic and anti-inflammatory drugs. It is currently under evaluation as a treatment for osteoarthritis (OA), the most common form of arthritis. Although phase III trials have been successfully completed in OA patients no dates for regulatory submission have yet been given.
Structure
Thumb
Synonyms
LCF
ML3000
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIP5T6BYS22Y
CAS number156897-06-2
WeightAverage: 379.879
Monoisotopic: 379.13390666
Chemical FormulaC23H22ClNO2
InChI KeyUAWXGRJVZSAUSZ-UHFFFAOYSA-N
InChI
InChI=1S/C23H22ClNO2/c1-23(2)13-19-22(15-6-4-3-5-7-15)21(16-8-10-17(24)11-9-16)18(12-20(26)27)25(19)14-23/h3-11H,12-14H2,1-2H3,(H,26,27)
IUPAC Name
2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid
SMILES
CC1(C)CN2C(CC(O)=O)=C(C(=C2C1)C1=CC=CC=C1)C1=CC=C(Cl)C=C1
Pharmacology
IndicationFor the management of osteoarthritis.
Structured Indications Not Available
PharmacodynamicsLicofelone belongs to a novel class of dual-acting anti-inflammatory drugs called COX/LO inhibitors. This group of drugs simultaneously inhibits the enzymes cyclooxygenase (COX) and 5-lipoxygenase (LO).
Mechanism of actionLicofelone, through combined 5-LOX/COX-inhibition, reduces levels of inflammatory prostaglandins and leukotrienes.
TargetKindPharmacological actionActionsOrganismUniProt ID
Arachidonate 5-lipoxygenaseProteinunknownNot AvailableHumanP09917 details
Prostaglandin G/H synthase 2ProteinunknownNot AvailableHumanP35354 details
Group IIE secretory phospholipase A2ProteinunknownNot AvailableHumanQ9NZK7 details
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
SubstrateEnzymesProduct
Licofelone
Licofelone acyl glucuronideDetails
Licofelone
Licofelone metabolite M4Details
Licofelone metabolite M4
Licofelone metabolite M5Details
Licofelone
Licofelone metabolite M2Details
Licofelone metabolite M2
Licofelone metabolite M3Details
Licofelone acyl glucuronide
Licofelone metabolite M3Details
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug Interactions
DrugInteractionDrug group
AbirateroneThe serum concentration of Licofelone can be increased when it is combined with Abiraterone.Approved
AmiodaroneThe metabolism of Licofelone can be decreased when combined with Amiodarone.Approved, Investigational
AmodiaquineThe serum concentration of Amodiaquine can be increased when it is combined with Licofelone.Approved
AprepitantThe metabolism of Licofelone can be increased when combined with Aprepitant.Approved, Investigational
CapecitabineThe metabolism of Licofelone can be decreased when combined with Capecitabine.Approved, Investigational
CarbamazepineThe metabolism of Licofelone can be increased when combined with Carbamazepine.Approved, Investigational
CelecoxibThe metabolism of Licofelone can be decreased when combined with Celecoxib.Approved, Investigational
CeritinibThe serum concentration of Licofelone can be increased when it is combined with Ceritinib.Approved
CholecalciferolThe metabolism of Licofelone can be decreased when combined with Cholecalciferol.Approved, Nutraceutical
ClopidogrelThe metabolism of Licofelone can be decreased when combined with Clopidogrel.Approved, Nutraceutical
ClotrimazoleThe metabolism of Licofelone can be decreased when combined with Clotrimazole.Approved, Vet Approved
CyclosporineThe metabolism of Licofelone can be decreased when combined with Cyclosporine.Approved, Investigational, Vet Approved
DabrafenibThe serum concentration of Licofelone can be decreased when it is combined with Dabrafenib.Approved
DeferasiroxThe serum concentration of Licofelone can be increased when it is combined with Deferasirox.Approved, Investigational
DelavirdineThe metabolism of Licofelone can be decreased when combined with Delavirdine.Approved
EfavirenzThe metabolism of Licofelone can be decreased when combined with Efavirenz.Approved, Investigational
EtravirineThe metabolism of Licofelone can be decreased when combined with Etravirine.Approved
FelodipineThe metabolism of Licofelone can be decreased when combined with Felodipine.Approved, Investigational
FloxuridineThe metabolism of Licofelone can be decreased when combined with Floxuridine.Approved
FluconazoleThe metabolism of Licofelone can be decreased when combined with Fluconazole.Approved
FluorouracilThe metabolism of Licofelone can be decreased when combined with Fluorouracil.Approved
FluvastatinThe metabolism of Licofelone can be decreased when combined with Fluvastatin.Approved
FluvoxamineThe metabolism of Licofelone can be decreased when combined with Fluvoxamine.Approved, Investigational
FosphenytoinThe metabolism of Licofelone can be increased when combined with Fosphenytoin.Approved
GemfibrozilThe metabolism of Licofelone can be decreased when combined with Gemfibrozil.Approved
IndinavirThe metabolism of Licofelone can be decreased when combined with Indinavir.Approved
IrbesartanThe metabolism of Licofelone can be decreased when combined with Irbesartan.Approved, Investigational
KetoconazoleThe metabolism of Licofelone can be decreased when combined with Ketoconazole.Approved, Investigational
LapatinibThe metabolism of Licofelone can be decreased when combined with Lapatinib.Approved, Investigational
LeflunomideThe metabolism of Licofelone can be decreased when combined with Leflunomide.Approved, Investigational
LopinavirThe metabolism of Licofelone can be decreased when combined with Lopinavir.Approved
LosartanThe metabolism of Licofelone can be decreased when combined with Losartan.Approved
LovastatinThe metabolism of Licofelone can be decreased when combined with Lovastatin.Approved, Investigational
LumacaftorThe serum concentration of Licofelone can be increased when it is combined with Lumacaftor.Approved
MifepristoneThe serum concentration of Licofelone can be increased when it is combined with Mifepristone.Approved, Investigational
NicardipineThe metabolism of Licofelone can be decreased when combined with Nicardipine.Approved
NilotinibThe metabolism of Licofelone can be decreased when combined with Nilotinib.Approved, Investigational
OmeprazoleThe metabolism of Licofelone can be decreased when combined with Omeprazole.Approved, Investigational, Vet Approved
PhenobarbitalThe metabolism of Licofelone can be increased when combined with Phenobarbital.Approved
PhenytoinThe metabolism of Licofelone can be increased when combined with Phenytoin.Approved, Vet Approved
PioglitazoneThe metabolism of Licofelone can be decreased when combined with Pioglitazone.Approved, Investigational
PrimidoneThe metabolism of Licofelone can be increased when combined with Primidone.Approved, Vet Approved
PyrimethamineThe metabolism of Licofelone can be decreased when combined with Pyrimethamine.Approved, Vet Approved
QuinineThe metabolism of Licofelone can be decreased when combined with Quinine.Approved
RabeprazoleThe metabolism of Licofelone can be decreased when combined with Rabeprazole.Approved, Investigational
RifampicinThe metabolism of Licofelone can be increased when combined with Rifampicin.Approved
RifapentineThe metabolism of Licofelone can be increased when combined with Rifapentine.Approved
RitonavirThe metabolism of Licofelone can be decreased when combined with Ritonavir.Approved, Investigational
RosiglitazoneThe metabolism of Licofelone can be decreased when combined with Rosiglitazone.Approved, Investigational
SecobarbitalThe metabolism of Licofelone can be increased when combined with Secobarbital.Approved, Vet Approved
SildenafilThe metabolism of Licofelone can be decreased when combined with Sildenafil.Approved, Investigational
SorafenibThe metabolism of Licofelone can be decreased when combined with Sorafenib.Approved, Investigational
StiripentolThe metabolism of Licofelone can be decreased when combined with Stiripentol.Approved
SulfadiazineThe metabolism of Licofelone can be decreased when combined with Sulfadiazine.Approved, Vet Approved
SulfamethoxazoleThe metabolism of Licofelone can be decreased when combined with Sulfamethoxazole.Approved
SulfisoxazoleThe metabolism of Licofelone can be decreased when combined with Sulfisoxazole.Approved, Vet Approved
TamoxifenThe metabolism of Licofelone can be decreased when combined with Tamoxifen.Approved
TeriflunomideThe metabolism of Licofelone can be decreased when combined with Teriflunomide.Approved
TicagrelorThe metabolism of Licofelone can be decreased when combined with Ticagrelor.Approved
TiclopidineThe metabolism of Licofelone can be decreased when combined with Ticlopidine.Approved
TolbutamideThe metabolism of Licofelone can be decreased when combined with Tolbutamide.Approved
TrimethoprimThe metabolism of Licofelone can be decreased when combined with Trimethoprim.Approved, Vet Approved
Valproic AcidThe metabolism of Licofelone can be decreased when combined with Valproic Acid.Approved, Investigational
ValsartanThe metabolism of Licofelone can be decreased when combined with Valsartan.Approved, Investigational
VoriconazoleThe metabolism of Licofelone can be decreased when combined with Voriconazole.Approved, Investigational
ZafirlukastThe metabolism of Licofelone can be decreased when combined with Zafirlukast.Approved, Investigational
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. Narayanan NK, Nargi D, Attur M, Abramson SB, Narayanan BA: Anticancer effects of licofelone (ML-3000) in prostate cancer cells. Anticancer Res. 2007 Jul-Aug;27(4B):2393-402. [PubMed:17695530 ]
  2. Kulkarni SK, Singh VP: Licofelone--a novel analgesic and anti-inflammatory agent. Curr Top Med Chem. 2007;7(3):251-63. [PubMed:17305568 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9088
Caco-2 permeable+0.5558
P-glycoprotein substrateNon-substrate0.522
P-glycoprotein inhibitor INon-inhibitor0.7895
P-glycoprotein inhibitor IINon-inhibitor0.5081
Renal organic cation transporterNon-inhibitor0.7022
CYP450 2C9 substrateNon-substrate0.7715
CYP450 2D6 substrateNon-substrate0.7635
CYP450 3A4 substrateSubstrate0.7167
CYP450 1A2 substrateInhibitor0.5308
CYP450 2C9 inhibitorNon-inhibitor0.6777
CYP450 2D6 inhibitorNon-inhibitor0.8277
CYP450 2C19 inhibitorInhibitor0.5281
CYP450 3A4 inhibitorNon-inhibitor0.9103
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6807
Ames testNon AMES toxic0.7968
CarcinogenicityNon-carcinogens0.6973
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6966 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9775
hERG inhibition (predictor II)Non-inhibitor0.6155
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00111 mg/mLALOGPS
logP5.39ALOGPS
logP5.72ChemAxon
logS-5.5ALOGPS
pKa (Strongest Acidic)4.83ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area42.23 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity108.79 m3·mol-1ChemAxon
Polarizability41.8 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as diphenylpyrroles. These are aromatic heterocyclic compounds with a structure based on a pyrrole ring linked to exactly two phenyl groups.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPyrroles
Sub ClassSubstituted pyrroles
Direct ParentDiphenylpyrroles
Alternative Parents
Substituents
  • 3,4-diphenylpyrrole
  • Pyrrolizine
  • Halobenzene
  • Chlorobenzene
  • Benzenoid
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • Azacycle
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Iron 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 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  2. Vidal C, Gomez-Hernandez A, Sanchez-Galan E, Gonzalez A, Ortega L, Gomez-Gerique JA, Tunon J, Egido J: Licofelone, a balanced inhibitor of cyclooxygenase and 5-lipoxygenase, reduces inflammation in a rabbit model of atherosclerosis. J Pharmacol Exp Ther. 2007 Jan;320(1):108-16. Epub 2006 Oct 2. [PubMed:17015640 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Prostaglandin-endoperoxide synthase activity
Specific Function:
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, p...
Gene Name:
PTGS2
Uniprot ID:
P35354
Molecular Weight:
68995.625 Da
References
  1. Vidal C, Gomez-Hernandez A, Sanchez-Galan E, Gonzalez A, Ortega L, Gomez-Gerique JA, Tunon J, Egido J: Licofelone, a balanced inhibitor of cyclooxygenase and 5-lipoxygenase, reduces inflammation in a rabbit model of atherosclerosis. J Pharmacol Exp Ther. 2007 Jan;320(1):108-16. Epub 2006 Oct 2. [PubMed:17015640 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Phospholipase a2 activity
Specific Function:
PA2 catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-phosphoglycerides. Has a preference for arachidonic-containing phospholipids.
Gene Name:
PLA2G2E
Uniprot ID:
Q9NZK7
Molecular Weight:
15988.525 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase 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, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
References
  1. 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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Steroid hydroxylase 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...
Gene Name:
CYP2C8
Uniprot ID:
P10632
Molecular Weight:
55824.275 Da
References
  1. 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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
This enzyme metabolizes arachidonic acid predominantly via a NADPH-dependent olefin epoxidation to all four regioisomeric cis-epoxyeicosatrienoic acids. One of the predominant enzymes responsible for the epoxidation of endogenous cardiac arachidonic acid pools.
Gene Name:
CYP2J2
Uniprot ID:
P51589
Molecular Weight:
57610.165 Da
References
  1. 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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function:
Not Available
Gene Name:
CYP2B7
Uniprot ID:
B6A7R5
Molecular Weight:
55876.31 Da
References
  1. 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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Retinoic acid binding
Specific Function:
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1.
Gene Name:
UGT1A3
Uniprot ID:
P35503
Molecular Weight:
60337.835 Da
References
  1. 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 ]
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Drug created on September 11, 2007 11:49 / Updated on August 17, 2016 12:24