Details of the Drug

General Information of Drug (ID: DM7HLFD)

• Drug Name: Licofelone
• Synonyms: LCF; Licofelone [INN]; ML 3000; ML-3000; [6-(4-CHLOROPHENYL)-2,2-DIMETHYL-7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZIN-5-YL]ACETIC ACID; (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)acetic acid; (6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)acetic acid; 2,2-Dimethyl-6-(4-chlorophenyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)acetic acid; 2,3-Dihydro-6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-1H-pyrrolizine-5-acetic acid; 2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,7-dihydropyrrolizin-3-yl]acetic acid; 6-(4-Chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizine-5-acetic acid

Indication

Disease Entry	ICD 11	Status	REF
Osteoarthritis	FA00-FA05	Discontinued in Phase 1	[1]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 1:
  Molecular Weight (mw); 379.9
  Topological Polar Surface Area (xlogp); 5.2
  Rotatable Bond Count (rotbonds); 4
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 2
• Chemical Identifiers:
  Formula: C23H22ClNO2
  IUPAC Name: 2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,7-dihydropyrrolizin-3-yl]acetic acid
  Canonical SMILES: CC1(CC2=C(C(=C(N2C1)CC(=O)O)C3=CC=C(C=C3)Cl)C4=CC=CC=C4)C
  InChI: 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)
  InChIKey: UAWXGRJVZSAUSZ-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 133021
  CAS Number: 156897-06-2
  DrugBank ID: DB04725
  TTD ID: D0N1SU
  INTEDE ID: DR0951

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Arachidonate 5-lipoxygenase (5-LOX)	TT2J34L	LOX5_HUMAN	Inhibitor	[2], [3], [4], [5]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Substrate	[6]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Substrate	[6]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Substrate	[7]

Molecular Expression Atlas of This Drug

• The Studied Disease: Osteoarthritis
• ICD Disease Classification: FA00-FA05

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Arachidonate 5-lipoxygenase (5-LOX)	DTT	ALOX5	4.15E-01	-0.06	-0.15
Cytochrome P450 2C8 (CYP2C8)	DME	CYP2C8	5.27E-01	-1.74E-02	-6.97E-02
Cytochrome P450 2C9 (CYP2C9)	DME	CYP2C9	4.97E-04	-1.04E+00	-1.67E+00

References

• [1] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003927)
• [2] Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) selectivity of COX inhibitors. Prostaglandins Leukot Essent Fatty Acids. 2008 Feb;78(2):99-108.
• [3] Activity and potential role of licofelone in the management of osteoarthritis. Clin Interv Aging. 2007;2(1):73-9.
• [4] Licofelone, a dual COX/5-LOX inhibitor, induces apoptosis in HCA-7 colon cancer cells through the mitochondrial pathway independently from its abil... Carcinogenesis. 2008 Feb;29(2):371-80.
• [5] 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. J Rheumatol. 2002 Jul;29(7):1446-53.
• [6] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [7] 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. Drug Metab Dispos. 2008 May;36(5):894-903.
• [8] Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
• [9] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [10] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [11] Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics. 2003 Sep;13(9):565-75.
• [12] Analysis of human cytochrome P450 2C8 substrate specificity using a substrate pharmacophore and site-directed mutants. Biochemistry. 2004 Dec 14;43(49):15379-92.
• [13] Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8.
• [14] PharmGKB summary: mycophenolic acid pathway. Pharmacogenet Genomics. 2014 Jan;24(1):73-9.
• [15] Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
• [16] Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
• [17] Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
• [18] Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003 Aug;144(8):3382-98.
• [19] Drug-drug interactions with imatinib: an observational study. Medicine (Baltimore). 2016 Oct;95(40):e5076.
• [20] Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 2000 Feb;28(2):125-30.
• [21] New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. Curr Drug Metab. 2009 Dec;10(10):1075-126.
• [22] A potential role for the estrogen-metabolizing cytochrome P450 enzymes in human breast carcinogenesis. Breast Cancer Res Treat. 2003 Dec;82(3):191-7.
• [23] A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
• [24] Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes. Drug Metab Dispos. 2005 Jul;33(7):1027-35.
• [25] Effect of aging on glucuronidation of valproic acid in human liver microsomes and the role of UDP-glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10. Drug Metab Dispos. 2009 Jan;37(1):229-36.
• [26] UGT1A1*28 is associated with decreased systemic exposure of atorvastatin lactone. Mol Diagn Ther. 2013 Aug;17(4):233-7.
• [27] Cerivastatin, genetic variants, and the risk of rhabdomyolysis. Pharmacogenet Genomics. 2011 May;21(5):280-8.
• [28] Pitavastatin: a review in hypercholesterolemia. Am J Cardiovasc Drugs. 2017 Apr;17(2):157-168.
• [29] Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10. Drug Metab Dispos. 2002 Dec;30(12):1462-9.
• [30] Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2011 Apr;89(4):524-8.
• [31] Pharmacogenomics of statins: understanding susceptibility to adverse effects. Pharmgenomics Pers Med. 2016 Oct 3;9:97-106.
• [32] 5-lipoxygenase inhibitor zileuton attenuates ischemic brain damage: involvement of matrix metalloproteinase 9. Neurol Res. 2009 Oct;31(8):848-52.
• [33] Inhibition of leukotriene formation by diethylcarbamazine modifies the acid-base balance in the rabbits with blast injuries of the lungs. Vojnosanit Pregl. 1999 May-Jun;56(3):243-7.
• [34] Anti-inflammatory and anti-arthritic activities of silymarin acting through inhibition of 5-lipoxygenase. Phytomedicine. 2000 Mar;7(1):21-4.
• [35] Phenidone protects the nigral dopaminergic neurons from LPS-induced neurotoxicity. Neurosci Lett. 2008 Nov 7;445(1):1-6.
• [36] Simple analogues of anthralin: unusual specificity of structure and antiproliferative activity. J Med Chem. 1997 Nov 7;40(23):3773-80.
• [37] Treatment with 5-lipoxygenase inhibitor VIA-2291 (Atreleuton) in patients with recent acute coronary syndrome. Circ Cardiovasc Imaging. 2010 May;3(3):298-307.
• [38] The in vitro free radical scavenging activity of tenidap, a new dual cyclo-oxygenase and 5-1ipoxygenase inhibitor. Mediators Inflamm. 1992;1(2):141-3.
• [39] FPL 62064, a topically active 5-lipoxygenase/cyclooxygenase inhibitor. Agents Actions. 1990 Jun;30(3-4):432-42.
• [40] Pharmacological profile of the novel potent antirheumatic 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid. Arzneimittelforschung. 1997 May;47(5):648-52.
• [41] Novel dual cyclooxygenase and lipoxygenase inhibitors targeting hyaluronan-CD44v6 pathway and inducing cytotoxicity in colon cancer cells. Bioorg Med Chem. 2013 May 1;21(9):2551-9.