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Details

Stereochemistry ACHIRAL
Molecular Formula C23H22ClNO2
Molecular Weight 379.879
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LICOFELONE

SMILES

CC1(C)CN2C(CC(O)=O)=C(C(=C2C1)C3=CC=CC=C3)C4=CC=C(Cl)C=C4

InChI

InChIKey=UAWXGRJVZSAUSZ-UHFFFAOYSA-N
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)

HIDE SMILES / InChI

Molecular Formula C23H22ClNO2
Molecular Weight 379.879
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/17305568 http://hktmc.com.cn/ChineseMedia/Magazine/Medicine/ajdmpk/AJDMPK-2010-4/AJPP%202010-4%20_287-299_%20ML3000.pdf

Licofelone (ML 3000) is a pyrrolizine derivative originally discovered by Merckle GmbH and developed by EuroAllaince with a unique pharmacological profile, which comprises optimal gastrointestinal tolerability and high analgesic and anti-inflammatory activity. These effects are due to balanced and selective inhibition of both cyclo-oxygenase and 5-lipoxygenase. Inhibition of 5-lipoxygenase may reduce the gastrointestinal toxicity associated with other non steroidal anti-inflammatory drugs, which only inhibit cyclooxygenase. Licofelone also has antipyretic and antiaggregatory properties. Clinical and preclinical trials were also undertaken for osteoarthritis, rheumatoid arthritis, asthma, pain and inflammation. However, development for these indications appear to have been discontinued.

CNS Activity

Curator's Comment: Almost no penetration of the blood-brain barrier was noted in animal study. No human data available.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.21 µM [IC50]
0.18 µM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Doses

Doses

DosePopulationAdverse events​
400 mg 2 times / day multiple, oral (unknown)
Highest studied dose
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources:
healthy, ADULT
n = 30
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 30
Sources:
Other AEs: fever, hot flashes...
Other AEs:
fever (6.7%)
hot flashes (6.7%)
dizzines (6.7%)
abdominal pain (26.7%)
diarrhea (50%)
Flatulence (13.3%)
coughing (13.3%)
rhinitis (16.6%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Flatulence 13.3%
400 mg 2 times / day multiple, oral (unknown)
Highest studied dose
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources:
healthy, ADULT
n = 30
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 30
Sources:
coughing 13.3%
400 mg 2 times / day multiple, oral (unknown)
Highest studied dose
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources:
healthy, ADULT
n = 30
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 30
Sources:
rhinitis 16.6%
400 mg 2 times / day multiple, oral (unknown)
Highest studied dose
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources:
healthy, ADULT
n = 30
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 30
Sources:
abdominal pain 26.7%
400 mg 2 times / day multiple, oral (unknown)
Highest studied dose
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources:
healthy, ADULT
n = 30
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 30
Sources:
diarrhea 50%
400 mg 2 times / day multiple, oral (unknown)
Highest studied dose
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources:
healthy, ADULT
n = 30
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 30
Sources:
dizzines 6.7%
400 mg 2 times / day multiple, oral (unknown)
Highest studied dose
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources:
healthy, ADULT
n = 30
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 30
Sources:
fever 6.7%
400 mg 2 times / day multiple, oral (unknown)
Highest studied dose
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources:
healthy, ADULT
n = 30
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 30
Sources:
hot flashes 6.7%
400 mg 2 times / day multiple, oral (unknown)
Highest studied dose
Dose: 400 mg, 2 times / day
Route: oral
Route: multiple
Dose: 400 mg, 2 times / day
Sources:
healthy, ADULT
n = 30
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 30
Sources:
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Dual inhibition of 5-lipoxygenase and cyclooxygenases 1 and 2 by ML3000 reduces joint destruction in adjuvant arthritis.
2001 Sep
Study of the role of leukotriene B()4 in abnormal function of human subchondral osteoarthritis osteoblasts: effects of cyclooxygenase and/or 5-lipoxygenase inhibition.
2002 Jul
International Conference on Inflammopharmacology -- VIII Side-Effects of Anti-inflammatory Drugs Symposium.
2003 Jul
COX-LOX inhibition: current evidence for an emerging new therapy.
2003 May
Safety of anti-inflammatory treatment--new ways of thinking.
2004 Feb
Gateways to clinical trials.
2004 Jan-Feb
Gateways to clinical trials.
2004 Sep
Pain and osteoarthritis: new drugs and mechanisms.
2004 Sep
The protective effect of licofelone on experimental osteoarthritis is correlated with the downregulation of gene expression and protein synthesis of several major cartilage catabolic factors: MMP-13, cathepsin K and aggrecanases.
2005
Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow.
2006
Anti-inflammatory effect of licofelone against various inflammatory challenges.
2006 Feb
Activity and potential role of licofelone in the management of osteoarthritis.
2007
Activation of proteinase-activated receptor 2 in human osteoarthritic cartilage upregulates catabolic and proinflammatory pathways capable of inducing cartilage degradation: a basic science study.
2007
DMOAD developments: present and future.
2007
Extracellular localization of galectin-3 has a deleterious role in joint tissues.
2007
Gastrointestinal safety of novel nonsteroidal antiinflammatory drugs: selective COX-2 inhibitors and beyond.
2007 Aug
Comparative protection against liver inflammation and fibrosis by a selective cyclooxygenase-2 inhibitor and a nonredox-type 5-lipoxygenase inhibitor.
2007 Dec
Selection of reliable reference genes for qPCR studies on chondroprotective action.
2007 Feb 26
Arthritis clinical trial results revealed.
2007 Jan 3
Anticancer effects of licofelone (ML-3000) in prostate cancer cells.
2007 Jul-Aug
Dynamic simulations on the arachidonic acid metabolic network.
2007 Mar 23
Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling.
2008
The dual inhibitor of lipoxygenase and cyclooxygenase ML3000 decreases the expression of CXCR3 ligands.
2008 Apr
Licofelone, a dual COX/5-LOX inhibitor, induces apoptosis in HCA-7 colon cancer cells through the mitochondrial pathway independently from its ability to affect the arachidonic acid cascade.
2008 Feb
Gateways to clinical trials.
2008 Mar
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.
2008 May
5-lipoxygenase: underappreciated role of a pro-inflammatory enzyme in tumorigenesis.
2010
High mobility group box 1 potentiates the pro-inflammatory effects of interleukin-1β in osteoarthritic synoviocytes.
2010
Regulation of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase-activating protein/5-lipoxygenase by 4-hydroxynonenal in human osteoarthritic chondrocytes.
2010
Relationship between bone marrow lesions, cartilage loss and pain in knee osteoarthritis: results from a randomised controlled clinical trial using MRI.
2010 Dec
Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.
2010 Dec
Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence.
2010 Oct
Anti-atherogenic effect of BHB-TZD having inhibitory activities on cyclooxygenase and 5-lipoxygenase in hyperlipidemic mice.
2010 Sep
Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase.
2011 Apr 28
Chemopreventive efficacy and mechanism of licofelone in a mouse lung tumor model via aspiration.
2011 Aug
Patents

Sample Use Guides

In a double-blind study, licofelone significantly improved the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and also pain, stiffness and disability relative to placebo in osteoarthritis patients when orally administered twice-daily at doses of 200mg and 400mg. A lower dose (100mg) was not sufficiently effective
Route of Administration: Oral
Using a human whole blood assay it was shown that 0.3-30 ug/ml licofelone (ML 3000) concentration-dependently inhibited the synthesis of PGE2 (IC50=3.9 uM) and 1-10 uM inhibited the synthesis of LTB4 in a concentration related manner (IC50=3.6 uM)
Substance Class Chemical
Created
by admin
on Fri Dec 15 15:37:21 GMT 2023
Edited
by admin
on Fri Dec 15 15:37:21 GMT 2023
Record UNII
P5T6BYS22Y
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
LICOFELONE
INN   MART.   MI  
INN  
Official Name English
licofelone [INN]
Common Name English
ML 3000
Common Name English
(6-(4-CHLOROPHENYL)-2,2-DIMETHYL-7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-5-YL)-ACETIC ACID
Systematic Name English
LICOFELONE [MART.]
Common Name English
LICOFELONE [MI]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C1323
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
Code System Code Type Description
EPA CompTox
DTXSID40166154
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
MESH
C088092
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
MERCK INDEX
m6803
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY Merck Index
FDA UNII
P5T6BYS22Y
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
INN
7786
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
SMS_ID
100000127672
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
DRUG BANK
DB04725
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
WIKIPEDIA
LICOFELONE
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
PUBCHEM
133021
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
ChEMBL
CHEMBL300982
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
EVMPD
SUB33729
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
CAS
156897-06-2
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
NCI_THESAURUS
C63957
Created by admin on Fri Dec 15 15:37:21 GMT 2023 , Edited by admin on Fri Dec 15 15:37:21 GMT 2023
PRIMARY
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