Identification

Name
Licofelone
Accession Number
DB04725
Type
Small Molecule
Groups
Investigational
Description

Developed 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
Categories
UNII
P5T6BYS22Y
CAS number
156897-06-2
Weight
Average: 379.879
Monoisotopic: 379.13390666
Chemical Formula
C23H22ClNO2
InChI Key
UAWXGRJVZSAUSZ-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

Indication

For the management of osteoarthritis.

Structured Indications
Not Available
Pharmacodynamics

Licofelone 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 action

Licofelone, through combined 5-LOX/COX-inhibition, reduces levels of inflammatory prostaglandins and leukotrienes.

TargetActionsOrganism
UGroup IIE secretory phospholipase A2Not AvailableHuman
UProstaglandin G/H synthase 2Not AvailableHuman
UArachidonate 5-lipoxygenaseNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not 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, Investigational
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
ClotrimazoleThe metabolism of Licofelone can be decreased when combined with Clotrimazole.Approved, Vet Approved
CrisaboroleThe metabolism of Licofelone can be decreased when combined with Crisaborole.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
DosulepinThe metabolism of Licofelone can be decreased when combined with Dosulepin.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
LobeglitazoneThe metabolism of Licofelone can be decreased when combined with Lobeglitazone.Approved, Investigational
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
ManidipineThe metabolism of Licofelone can be decreased when combined with Manidipine.Approved, Investigational
MidostaurinThe metabolism of Licofelone can be decreased when combined with Midostaurin.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
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
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
TopiroxostatThe metabolism of Licofelone can be decreased when combined with Topiroxostat.Approved, Investigational
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 Interactions
Not Available

References

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
PubChem Compound
133021
PubChem Substance
175426859
ChemSpider
117391
BindingDB
50038649
ChEMBL
CHEMBL300982
HET
LCF
PDB Entries
1zyx / 4g8h

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 Solubility0.00111 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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyrroles
Sub Class
Substituted pyrroles
Direct Parent
Diphenylpyrroles
Alternative Parents
Pyrrolizines / Chlorobenzenes / Aryl chlorides / Heteroaromatic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organochlorides
show 3 more
Substituents
3,4-diphenylpyrrole / Pyrrolizine / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Heteroaromatic compound / Carboxylic acid derivative
show 14 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

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
Uniprot Name
Group IIE secretory phospholipase A2
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]
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...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
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
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
Uniprot Name
Arachidonate 5-lipoxygenase
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]

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 un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
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
Substrate
Inhibitor
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 un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
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 f...
Gene Name
CYP2J2
Uniprot ID
P51589
Uniprot Name
Cytochrome P450 2J2
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
Uniprot Name
Cytochrome P450 2B7 isoform
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 reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
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]

Drug created on September 11, 2007 11:49 / Updated on November 09, 2017 03:46