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
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)
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 |
DescriptionSources: http://adisinsight.springer.com/drugs/800003927Curator'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
Sources: http://adisinsight.springer.com/drugs/800003927
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
Sources: http://hktmc.com.cn/ChineseMedia/Magazine/Medicine/ajdmpk/AJDMPK-2010-4/AJPP%202010-4%20_287-299_%20ML3000.pdf
Curator's Comment: Almost no penetration of the blood-brain barrier was noted in animal study. No human data available.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2094253 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17305568 |
0.21 µM [IC50] | ||
Target ID: CHEMBL215 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17305568 |
0.18 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Doses
Dose | Population | Adverse 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%) Sources: hot flashes (6.7%) dizzines (6.7%) abdominal pain (26.7%) diarrhea (50%) Flatulence (13.3%) coughing (13.3%) rhinitis (16.6%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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: |
PubMed
Title | Date | PubMed |
---|---|---|
The gastrointestinal tolerability of the LOX/COX inhibitor, licofelone, is similar to placebo and superior to naproxen therapy in healthy volunteers: results from a randomized, controlled trial. | 2004 Apr |
|
Regulation of the expression of 5-lipoxygenase-activating protein/5-lipoxygenase and the synthesis of leukotriene B(4) in osteoarthritic chondrocytes: role of transforming growth factor beta and eicosanoids. | 2004 Dec |
|
Safety of anti-inflammatory treatment--new ways of thinking. | 2004 Feb |
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Osteoarthritis therapy--are there still unmet needs? | 2004 Feb |
|
Inhibition of gastric H,K-ATPase activity and gastric epithelial cell IL-8 secretion by the pyrrolizine derivative ML 3000. | 2004 Feb 10 |
|
Licofelone, an inhibitor of cyclooxygenase and 5-lipoxygenase, specifically inhibits cyclooxygenase-1-dependent platelet activation. | 2004 Mar 19 |
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Gateways to clinical trials. | 2004 Sep |
|
Pain and osteoarthritis: new drugs and mechanisms. | 2004 Sep |
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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 |
|
Leukotriene and prostaglandin synthesis pathways in osteoarthritic synovial membranes: regulating factors for interleukin 1beta synthesis. | 2005 Apr |
|
Superiority of the gastroduodenal safety profile of licofelone over rofecoxib, a COX-2 selective inhibitor, in dogs. | 2005 Feb |
|
Licofelone, a novel 5-LOX/COX-inhibitor, attenuates leukocyte rolling and adhesion on endothelium under flow. | 2005 Jul 1 |
|
The regulation of human MMP-13 by licofelone, an inhibitor of cyclo-oxygenases and 5-lipoxygenase, in human osteoarthritic chondrocytes is mediated by the inhibition of the p38 MAP kinase signalling pathway. | 2005 Jun |
|
Dual inhibition of cyclo-oxygenases and 5-lipoxygenase: a novel therapeutic approach to inflammation? | 2005 May |
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Eicosanoids, osteoarthritis, and crystal deposition diseases. | 2005 May |
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Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow. | 2006 |
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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 |
|
Activity and potential role of licofelone in the management of osteoarthritis. | 2007 |
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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 |
|
Extracellular localization of galectin-3 has a deleterious role in joint tissues. | 2007 |
|
Licofelone--a novel analgesic and anti-inflammatory agent. | 2007 |
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Efficacy of licofelone in dogs with clinical osteoarthritis. | 2007 Apr 28 |
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Selection of reliable reference genes for qPCR studies on chondroprotective action. | 2007 Feb 26 |
|
Anticancer effects of licofelone (ML-3000) in prostate cancer cells. | 2007 Jul-Aug |
|
Dynamic simulations on the arachidonic acid metabolic network. | 2007 Mar 23 |
|
Combination Therapy of PPARgamma Ligands and Inhibitors of Arachidonic Acid in Lung Cancer. | 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 target of arachidonic acid pathway is a new anticancer strategy for human prostate cancer. | 2008 Dec |
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Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) selectivity of COX inhibitors. | 2008 Feb |
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A role for subchondral bone changes in the process of osteoarthritis; a micro-CT study of two canine models. | 2008 Feb 12 |
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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 |
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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 |
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An exploration of the ability of tepoxalin to ameliorate the degradation of articular cartilage in a canine in vitro model. | 2009 Jul 22 |
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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 |
Sample Use Guides
In Vivo Use Guide
Sources: http://adisinsight.springer.com/drugs/800003927
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
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12005204
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
Edited
Fri Dec 16 17:39:19 UTC 2022
by
admin
on
Fri Dec 16 17:39:19 UTC 2022
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Record UNII |
P5T6BYS22Y
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Record Status |
Validated (UNII)
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Record Version |
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C1323
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C63957
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Tmax | PHARMACOKINETIC |
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