LICOFELONE

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 Search

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
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Cyclooxygenase 89 Target ID: CHEMBL2094253 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17305568	Inhibitor 8146		0.21 µM [IC50]
Arachidonate 5-lipoxygenase 49 Target ID: CHEMBL215 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17305568	Inhibitor 8146		0.18 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Osteoarthritis 155 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Phase III 651	Unknown Approved Use Unknown
Rheumatoid arthritis 310 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Preclinical	Unknown Approved Use Unknown
Pain 607 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Phase II 1133	Unknown Approved Use Unknown
Inflammation 101 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Phase II 1133	Unknown Approved Use Unknown

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: https://pubmed.ncbi.nlm.nih.gov/15089890	healthy, ADULT n = 30 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/15089890	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: https://pubmed.ncbi.nlm.nih.gov/15089890

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: https://pubmed.ncbi.nlm.nih.gov/15089890	healthy, ADULT n = 30 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/15089890
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: https://pubmed.ncbi.nlm.nih.gov/15089890	healthy, ADULT n = 30 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/15089890
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: https://pubmed.ncbi.nlm.nih.gov/15089890	healthy, ADULT n = 30 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/15089890
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: https://pubmed.ncbi.nlm.nih.gov/15089890	healthy, ADULT n = 30 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/15089890
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: https://pubmed.ncbi.nlm.nih.gov/15089890	healthy, ADULT n = 30 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/15089890
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: https://pubmed.ncbi.nlm.nih.gov/15089890	healthy, ADULT n = 30 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/15089890
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: https://pubmed.ncbi.nlm.nih.gov/15089890	healthy, ADULT n = 30 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/15089890
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: https://pubmed.ncbi.nlm.nih.gov/15089890	healthy, ADULT n = 30 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/15089890

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P001PID	https://www.1pchem.com/search?query=1P001PID
AK Scientific	B699	https://aksci.com/item_detail.php?cat=B699
AOBIOUS INC	AOB3889	http://aobious.com/aobious/search?search_query=AOB3889
Angene	AGN-PC-07Y4OS	http://www.angenechemical.com/productshow/AGN-PC-07Y4OS.html
ApexBio Technology	B1448	https://www.apexbt.com/catalogsearch/result/?q=B1448
AstaTech	C14938	http://astatechinc.com/CPSResult.php?CRNO=C14938
BLD Pharm	BD305628	http://www.bldpharm.com/search/Search.html?keyword=BD305628
BOC Sciences	156897-06-2	http://www.bocsci.com/description.asp?cas=156897-06-2
Cayman Chemical	10007692	http://www.caymanchem.com/app/template/Product.vm/catalog/10007692
Chem Scene	CS-0013159	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0013159
Hairui	HR105071	http://www.hairuichem.com/en/product/search.do?q=HR105071
KeyOrganics	AS-73938	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-73938
Lab Network	LN01287863	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01287863
Lab Seeker	SC-20109	http://www.labseeker.com/search.php?keywords=SC-20109&category=0
LabSeeker	SC-20109	http://www.labseeker.com/search.php?keywords=SC-20109&category=0
MedChem Express	HY-B1452	https://www.medchemexpress.com/search.html?q=HY-B1452&ft=&fa=&fp=
MolPort	MolPort-006-169-990	https://www.molport.com/shop/molecule-link/MolPort-006-169-990
MuseChem	R009348	https://www.musechem.com/product/R009348.html
ShangHai Biochempartner	BCP06598	http://www.biochempartner.com/search_BCP06598
Toronto Research Chemicals	L397730	https://www.trc-canada.com/product-detail/?CatNum=L397730
eMolecules	6697560	https://orderbb.emolecules.com/search/#?query=6697560
eNovation Chemicals	D491447	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D491447&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-5104424173	https://mcule.com/MCULE-5104424173/

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	15089890
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	15593193
Safety of anti-inflammatory treatment--new ways of thinking.	2004 Feb	14752171
Osteoarthritis therapy--are there still unmet needs?	2004 Feb	14752170
Inhibition of gastric H,K-ATPase activity and gastric epithelial cell IL-8 secretion by the pyrrolizine derivative ML 3000.	2004 Feb 10	15028114
Licofelone, an inhibitor of cyclooxygenase and 5-lipoxygenase, specifically inhibits cyclooxygenase-1-dependent platelet activation.	2004 Mar 19	15044038
Gateways to clinical trials.	2004 Sep	15538546
Pain and osteoarthritis: new drugs and mechanisms.	2004 Sep	15314506
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	16207326
Leukotriene and prostaglandin synthesis pathways in osteoarthritic synovial membranes: regulating factors for interleukin 1beta synthesis.	2005 Apr	15801029
Superiority of the gastroduodenal safety profile of licofelone over rofecoxib, a COX-2 selective inhibitor, in dogs.	2005 Feb	15720519
Licofelone, a novel 5-LOX/COX-inhibitor, attenuates leukocyte rolling and adhesion on endothelium under flow.	2005 Jul 1	15894291
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	15498796
Dual inhibition of cyclo-oxygenases and 5-lipoxygenase: a novel therapeutic approach to inflammation?	2005 May	15850989
Eicosanoids, osteoarthritis, and crystal deposition diseases.	2005 May	15838249
Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow.	2006	16569256
Effects on primary haemostasis of an anti-inflammatory agent with 5-lipoxygenase and cyclooxygenase inhibitory activity.	2006 Dec	17122671
Licofelone reduces progression of structural changes in a canine model of osteoarthritis under curative conditions: effect on protease expression and activity.	2006 Jun	16652435
Activity and potential role of licofelone in the management of osteoarthritis.	2007	18044077
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	18031579
Extracellular localization of galectin-3 has a deleterious role in joint tissues.	2007	17326835
Licofelone--a novel analgesic and anti-inflammatory agent.	2007	17305568
Efficacy of licofelone in dogs with clinical osteoarthritis.	2007 Apr 28	17468321
Selection of reliable reference genes for qPCR studies on chondroprotective action.	2007 Feb 26	17324259
Anticancer effects of licofelone (ML-3000) in prostate cancer cells.	2007 Jul-Aug	17695530
Dynamic simulations on the arachidonic acid metabolic network.	2007 Mar 23	17381237
Combination Therapy of PPARgamma Ligands and Inhibitors of Arachidonic Acid in Lung Cancer.	2008	19277204
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	18578867
The target of arachidonic acid pathway is a new anticancer strategy for human prostate cancer.	2008 Dec	19707453
Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) selectivity of COX inhibitors.	2008 Feb	18280718
A role for subchondral bone changes in the process of osteoarthritis; a micro-CT study of two canine models.	2008 Feb 12	18269731
Licofelone: the answer to unmet needs in osteoarthritis therapy?	2008 Jan	18457611
Gateways to clinical trials.	2008 Jan-Feb	18389098
Is collagenase-3 (MMP-13) expression in chondrosarcoma of the jaws a true marker for tumor aggressiveness?	2008 Jun 13	18554405
Gateways to clinical trials.	2008 Mar	18560631
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	18268076
Licofelone suppresses prostaglandin E2 formation by interference with the inducible microsomal prostaglandin E2 synthase-1.	2008 Sep	18550688
An exploration of the ability of tepoxalin to ameliorate the degradation of articular cartilage in a canine in vitro model.	2009 Jul 22	19624842
5-lipoxygenase: underappreciated role of a pro-inflammatory enzyme in tumorigenesis.	2010	21833182
Oestrogen is important for maintenance of cartilage and subchondral bone in a murine model of knee osteoarthritis.	2010	20923566
High mobility group box 1 potentiates the pro-inflammatory effects of interleukin-1β in osteoarthritic synoviocytes.	2010	20799933
Regulation of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase-activating protein/5-lipoxygenase by 4-hydroxynonenal in human osteoarthritic chondrocytes.	2010	20144213
Relationship between bone marrow lesions, cartilage loss and pain in knee osteoarthritis: results from a randomised controlled clinical trial using MRI.	2010 Dec	20610445
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	20570834
Upregulation of MMP-13 and TIMP-1 expression in response to mechanical strain in MC3T3-E1 osteoblastic cells.	2010 Nov 17	21080973
Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence.	2010 Oct	20697819
Anti-atherogenic effect of BHB-TZD having inhibitory activities on cyclooxygenase and 5-lipoxygenase in hyperlipidemic mice.	2010 Sep	20684827
Investigational pharmacology for low back pain.	2010 Sep 6	21197321
Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase.	2011 Apr 28	21434686
Chemopreventive efficacy and mechanism of licofelone in a mouse lung tumor model via aspiration.	2011 Aug	21562034

Patents

Sample Use Guides

In Vivo Use Guide

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

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 16 17:39:19 UTC 2022` Edited by `admin` on `Fri Dec 16 17:39:19 UTC 2022`
Record UNII	P5T6BYS22Y
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

LICOFELONE

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