LICOFELONE

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 Search

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
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 88 Target ID: CHEMBL2094253 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17305568	Inhibitor 7728		0.21 µM [IC50]
Arachidonate 5-lipoxygenase 48 Target ID: CHEMBL215 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17305568	Inhibitor 7728		0.18 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Osteoarthritis 151 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Phase III 643	Unknown Approved Use Unknown
Rheumatoid arthritis 294 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Preclinical	Unknown Approved Use Unknown
Pain 580 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Phase II 1101	Unknown Approved Use Unknown
Inflammation 99 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Phase II 1101	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
Dual inhibition of 5-lipoxygenase and cyclooxygenases 1 and 2 by ML3000 reduces joint destruction in adjuvant arthritis.	2001 Sep	11550975
[Double blockade should protect the stomach. New approach to rheumatism].	2001 Sep 20	11601098
Antithrombotic and platelet function inhibiting effects of ML3000, a new antiinflammatory drug with Cox/5-LOX inhibitory activity.	2002 Mar	12005203
Gateways to clinical trials.	2002 Oct	12500432
Gateways to clinical trials.	2003 Dec	14735233
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
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	15003800
Gateways to clinical trials.	2004 Sep	15538546
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
Effect of licofelone against NSAIDs-induced gastrointestinal ulceration and inflammation.	2005 Mar	15816411
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
Efficacy of licofelone in dogs with clinical osteoarthritis.	2007 Apr 28	17468321
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
The molecular mechanism of the inhibition by licofelone of the biosynthesis of 5-lipoxygenase products.	2007 Oct	17704828
Finding multiple target optimal intervention in disease-related molecular network.	2008	18985027
Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) selectivity of COX inhibitors.	2008 Feb	18280718
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
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	19291317
Anti-atherogenic effect of BHB-TZD having inhibitory activities on cyclooxygenase and 5-lipoxygenase in hyperlipidemic mice.	2010 Sep	20684827
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 `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

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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