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Details

Stereochemistry ACHIRAL
Molecular Formula C23H22ClNO2
Molecular Weight 379.8801
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LICOFELONE

SMILES

CC1(C)Cc2c(-c3ccccc3)c(-c4ccc(cc4)Cl)c(CC(=O)O)n2C1

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 379.8801
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
Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow.
2006
Effects on primary haemostasis of an anti-inflammatory agent with 5-lipoxygenase and cyclooxygenase inhibitory activity.
2006 Dec
Licofelone reduces progression of structural changes in a canine model of osteoarthritis under curative conditions: effect on protease expression and activity.
2006 Jun
The lipoxygenase-cyclooxygenase inhibitor licofelone prevents thromboxane A2-mediated cardiovascular derangement triggered by the inflammatory peptide fMLP in the rabbit.
2006 Sep 28
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
Licofelone--a novel analgesic and anti-inflammatory agent.
2007
Efficacy of licofelone in dogs with clinical osteoarthritis.
2007 Apr 28
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
Licofelone, a balanced inhibitor of cyclooxygenase and 5-lipoxygenase, reduces inflammation in a rabbit model of atherosclerosis.
2007 Jan
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
The molecular mechanism of the inhibition by licofelone of the biosynthesis of 5-lipoxygenase products.
2007 Oct
Combination Therapy of PPARgamma Ligands and Inhibitors of Arachidonic Acid in Lung Cancer.
2008
Analysis of the precision and sensitivity to change of different approaches to assess cartilage loss by quantitative MRI in a longitudinal multicentre clinical trial in patients with knee osteoarthritis.
2008
Finding multiple target optimal intervention in disease-related molecular network.
2008
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
The target of arachidonic acid pathway is a new anticancer strategy for human prostate cancer.
2008 Dec
Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) selectivity of COX inhibitors.
2008 Feb
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
A role for subchondral bone changes in the process of osteoarthritis; a micro-CT study of two canine models.
2008 Feb 12
Licofelone: the answer to unmet needs in osteoarthritis therapy?
2008 Jan
Gateways to clinical trials.
2008 Jan-Feb
Is collagenase-3 (MMP-13) expression in chondrosarcoma of the jaws a true marker for tumor aggressiveness?
2008 Jun 13
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
Licofelone suppresses prostaglandin E2 formation by interference with the inducible microsomal prostaglandin E2 synthase-1.
2008 Sep
Treatment with ephrin B2 positively impacts the abnormal metabolism of human osteoarthritic chondrocytes.
2009
Protective effects of total fraction of avocado/soybean unsaponifiables on the structural changes in experimental dog osteoarthritis: inhibition of nitric oxide synthase and matrix metalloproteinase-13.
2009
Systematic review of the management of canine osteoarthritis.
2009 Apr 4
An exploration of the ability of tepoxalin to ameliorate the degradation of articular cartilage in a canine in vitro model.
2009 Jul 22
Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI.
2009 Jun
5-lipoxygenase: underappreciated role of a pro-inflammatory enzyme in tumorigenesis.
2010
Oestrogen is important for maintenance of cartilage and subchondral bone in a murine model of knee osteoarthritis.
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
Upregulation of MMP-13 and TIMP-1 expression in response to mechanical strain in MC3T3-E1 osteoblastic cells.
2010 Nov 17
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
Investigational pharmacology for low back pain.
2010 Sep 6
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 Sat Jun 26 02:40:52 UTC 2021
Edited
by admin
on Sat Jun 26 02:40:52 UTC 2021
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 Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
Code System Code Type Description
EPA CompTox
156897-06-2
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
MESH
C088092
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
MERCK INDEX
M6803
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY Merck Index
FDA UNII
P5T6BYS22Y
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
INN
7786
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
DRUG BANK
DB04725
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
WIKIPEDIA
LICOFELONE
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
PUBCHEM
133021
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
ChEMBL
CHEMBL300982
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
EVMPD
SUB33729
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
CAS
156897-06-2
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
NCI_THESAURUS
C63957
Created by admin on Sat Jun 26 02:40:53 UTC 2021 , Edited by admin on Sat Jun 26 02:40:53 UTC 2021
PRIMARY
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