Licofelone

Identification

Generic Name
Licofelone
DrugBank Accession Number
DB04725
Background

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.

Type
Small Molecule
Groups
Investigational
Structure
Weight
Average: 379.879
Monoisotopic: 379.13390666
Chemical Formula
C23H22ClNO2
Synonyms
  • Licofelone
External IDs
  • ML 3000
  • ML-3000
  • ML3000

Pharmacology

Indication

For the management of osteoarthritis.

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Contraindications & Blackbox Warnings
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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
UArachidonate 5-lipoxygenaseNot AvailableHumans
UProstaglandin G/H synthase 2Not AvailableHumans
UGroup IIE secretory phospholipase A2Not AvailableHumans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Hover over products below to view reaction partners

Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe metabolism of Licofelone can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Licofelone is combined with Abciximab.
AbirateroneThe metabolism of Licofelone can be decreased when combined with Abiraterone.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Licofelone.
AcebutololLicofelone may decrease the antihypertensive activities of Acebutolol.
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
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 / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Chlorobenzene
show 14 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
P5T6BYS22Y
CAS number
156897-06-2
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

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. [Article]
  2. Kulkarni SK, Singh VP: Licofelone--a novel analgesic and anti-inflammatory agent. Curr Top Med Chem. 2007;7(3):251-63. [Article]
PubChem Compound
133021
PubChem Substance
175426859
ChemSpider
117391
BindingDB
50038649
ChEMBL
CHEMBL300982
ZINC
ZINC000003805769
PDBe Ligand
LCF
Wikipedia
Licofelone
PDB Entries
1zyx / 4g8h

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

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)4.8Chemaxon
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/MSsplash10-001i-0009000000-47bd454884c9f9f82313
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0059-0009000000-8a844ccc18a7c7e8b9cf
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0059-0009000000-c393ef534560e57c2edc
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0009000000-02474ab24844ed7bfe4c
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-01x9-0259000000-513994b3393003431a4e
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-02u0-7962000000-21740e19da9346f8513b
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-182.52277
predicted
DeepCCS 1.0 (2019)
[M+H]+184.88078
predicted
DeepCCS 1.0 (2019)
[M+Na]+191.87202
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]

Enzymes

Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
  2. Albrecht W, Unger A, Nussler AK, Laufer S: In vitro metabolism of 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid (licofelone, ML3000), an inhibitor of cyclooxygenase-1 and -2 and 5-lipoxygenase. Drug Metab Dispos. 2008 May;36(5):894-903. doi: 10.1124/dmd.108.020347. Epub 2008 Feb 11. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]

Drug created at September 11, 2007 17:49 / Updated at February 21, 2021 18:51