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 |
---|---|---|
Licofelone (ML-3000), a dual inhibitor of 5-lipoxygenase and cyclooxygenase, reduces the level of cartilage chondrocyte death in vivo in experimental dog osteoarthritis: inhibition of pro-apoptotic factors. | 2002 Jul |
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Gateways to clinical trials. | 2002 Oct |
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Licofelone (Merckle). | 2003 Aug |
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Evidence that 5-lipoxygenase and acetylated cyclooxygenase 2-derived eicosanoids regulate leukocyte-endothelial adherence in response to aspirin. | 2003 Aug |
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Gateways to clinical trials. | 2003 Dec |
|
The metabolic effects of inhibitors of 5-lipoxygenase and of cyclooxygenase 1 and 2 are an advancement in the efficacy and safety of anti-inflammatory therapy. | 2003 Jul |
|
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 |
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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 |
|
Licofelone--clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis. | 2004 Feb |
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Safety of anti-inflammatory treatment--new ways of thinking. | 2004 Feb |
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Osteoarthritis therapy--are there still unmet needs? | 2004 Feb |
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Is licofelone, a dual inhibitor of cyclo-oxygenase and 5-lipoxygenase, a promising alternative in anti-inflammatory therapy? | 2004 Feb |
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Inhibition of gastric H,K-ATPase activity and gastric epithelial cell IL-8 secretion by the pyrrolizine derivative ML 3000. | 2004 Feb 10 |
|
Treatment with licofelone prevents abnormal subchondral bone cell metabolism in experimental dog osteoarthritis. | 2004 Jan |
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Gateways to clinical trials. | 2004 Jan-Feb |
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The inhibition of subchondral bone resorption in the early phase of experimental dog osteoarthritis by licofelone is associated with a reduction in the synthesis of MMP-13 and cathepsin K. | 2004 Mar |
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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 |
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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 |
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Combined lipoxygenase/cyclo-oxygenase inhibition in the elderly: the example of licofelone. | 2005 |
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Superiority of the gastroduodenal safety profile of licofelone over rofecoxib, a COX-2 selective inhibitor, in dogs. | 2005 Feb |
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Licofelone, a novel 5-LOX/COX-inhibitor, attenuates leukocyte rolling and adhesion on endothelium under flow. | 2005 Jul 1 |
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Eicosanoids, osteoarthritis, and crystal deposition diseases. | 2005 May |
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Effect of licofelone against mechanical hyperalgesia and cold allodynia in the rat model of incisional pain. | 2005 May-Jun |
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Effects on primary haemostasis of an anti-inflammatory agent with 5-lipoxygenase and cyclooxygenase inhibitory activity. | 2006 Dec |
|
The lipoxygenase-cyclooxygenase inhibitor licofelone prevents thromboxane A2-mediated cardiovascular derangement triggered by the inflammatory peptide fMLP in the rabbit. | 2006 Sep 28 |
|
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 |
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Extracellular localization of galectin-3 has a deleterious role in joint tissues. | 2007 |
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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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Gastrointestinal safety of novel nonsteroidal antiinflammatory drugs: selective COX-2 inhibitors and beyond. | 2007 Aug |
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Comparative protection against liver inflammation and fibrosis by a selective cyclooxygenase-2 inhibitor and a nonredox-type 5-lipoxygenase inhibitor. | 2007 Dec |
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Selection of reliable reference genes for qPCR studies on chondroprotective action. | 2007 Feb 26 |
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Arthritis clinical trial results revealed. | 2007 Jan 3 |
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Anticancer effects of licofelone (ML-3000) in prostate cancer cells. | 2007 Jul-Aug |
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Combination Therapy of PPARgamma Ligands and Inhibitors of Arachidonic Acid in Lung Cancer. | 2008 |
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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 |
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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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Licofelone: the answer to unmet needs in osteoarthritis therapy? | 2008 Jan |
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Licofelone suppresses prostaglandin E2 formation by interference with the inducible microsomal prostaglandin E2 synthase-1. | 2008 Sep |
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Treatment with ephrin B2 positively impacts the abnormal metabolism of human osteoarthritic chondrocytes. | 2009 |
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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 |
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Regulation of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase-activating protein/5-lipoxygenase by 4-hydroxynonenal in human osteoarthritic chondrocytes. | 2010 |
|
Upregulation of MMP-13 and TIMP-1 expression in response to mechanical strain in MC3T3-E1 osteoblastic cells. | 2010 Nov 17 |
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Investigational pharmacology for low back pain. | 2010 Sep 6 |
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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 15 15:37:21 GMT 2023
by
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on
Fri Dec 15 15:37:21 GMT 2023
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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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Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Tmax | PHARMACOKINETIC |
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