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:: 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 87 Target ID: CHEMBL2094253 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17305568	Inhibitor 7701	Osteoarthritis Rheumatoid arthritis Pain Inflammation	0.209999999999999992 µM [IC50]
Arachidonate 5-lipoxygenase 48 Target ID: CHEMBL215 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17305568	Inhibitor 7701	Inflammation Pain Rheumatoid arthritis Osteoarthritis	0.179999999999999993 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase
Osteoarthritis 152 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Cyclooxygenase Arachidonate 5-lipoxygenase	Phase III 650
Rheumatoid arthritis 294 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Cyclooxygenase Arachidonate 5-lipoxygenase	Preclinical
Pain 580 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Cyclooxygenase Arachidonate 5-lipoxygenase	Phase II
Inflammation 99 Sources: http://adisinsight.springer.com/drugs/800003927	Primary	Cyclooxygenase Arachidonate 5-lipoxygenase	Phase II

PubMed

Title	Date	PubMed
In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: suppression of collagenase 1 and interleukin-1beta synthesis.	2001 Oct	11665972
[Double blockade should protect the stomach. New approach to rheumatism].	2001 Sep 20	11601098
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	12136904
Study of the role of leukotriene B()4 in abnormal function of human subchondral osteoarthritis osteoblasts: effects of cyclooxygenase and/or 5-lipoxygenase inhibition.	2002 Jul	12124864
The mechanism of action of the new antiinflammatory compound ML3000: inhibition of 5-LOX and COX-1/2.	2002 Mar	12005204
Gateways to clinical trials.	2002 Oct	12500432
Licofelone, a dual lipoxygenase-cyclooxygenase inhibitor, downregulates polymorphonuclear leukocyte and platelet function.	2002 Oct 18	12393068
Licofelone (Merckle).	2003 Aug	12917777
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	14518558
International Conference on Inflammopharmacology -- VIII Side-Effects of Anti-inflammatory Drugs Symposium.	2003 Jul	12831358
Anti arthritic drugs--SMi conference: dual inhibitors. 28-29 April 2003, London, UK.	2003 Jun	12861983
Relative contribution of acetylated cyclo-oxygenase (COX)-2 and 5-lipooxygenase (LOX) in regulating gastric mucosal integrity and adaptation to aspirin.	2003 Jun	12709408
COX-LOX inhibition: current evidence for an emerging new therapy.	2003 May	12800462
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
Is licofelone, a dual inhibitor of cyclo-oxygenase and 5-lipoxygenase, a promising alternative in anti-inflammatory therapy?	2004 Feb	14748764
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
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
Effects on primary haemostasis of an anti-inflammatory agent with 5-lipoxygenase and cyclooxygenase inhibitory activity.	2006 Dec	17122671
Anti-inflammatory effect of licofelone against various inflammatory challenges.	2006 Feb	16448396
Licofelone reduces progression of structural changes in a canine model of osteoarthritis under curative conditions: effect on protease expression and activity.	2006 Jun	16652435
DMOAD developments: present and future.	2007	17922676
Licofelone--a novel analgesic and anti-inflammatory agent.	2007	17305568
Efficacy of licofelone in dogs with clinical osteoarthritis.	2007 Apr 28	17468321
Comparative protection against liver inflammation and fibrosis by a selective cyclooxygenase-2 inhibitor and a nonredox-type 5-lipoxygenase inhibitor.	2007 Dec	17766677
Selection of reliable reference genes for qPCR studies on chondroprotective action.	2007 Feb 26	17324259
Dynamic simulations on the arachidonic acid metabolic network.	2007 Mar 23	17381237
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	18986534
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
Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) selectivity of COX inhibitors.	2008 Feb	18280718
Licofelone: the answer to unmet needs in osteoarthritis therapy?	2008 Jan	18457611
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
Licofelone suppresses prostaglandin E2 formation by interference with the inducible microsomal prostaglandin E2 synthase-1.	2008 Sep	18550688
Systematic review of the management of canine osteoarthritis.	2009 Apr 4	19346540
An exploration of the ability of tepoxalin to ameliorate the degradation of articular cartilage in a canine in vitro model.	2009 Jul 22	19624842
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	18653484
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
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 `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