Diacerein

Identification

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Name
Diacerein
Accession Number
DB11994
Type
Small Molecule
Groups
Approved, Investigational
Description

Diacerein is a prodrug which is metabolized to rhein. It is currently approved in France for the treatment of osteoarthritis although the use of diacerein is restricted due to the side effects including sevre diarrhea 6. Diacerein is under investigation for the treatment of Insulin Resistance, Diabetes Mellitus (Type 2), and Diabetes-Related Complications.

Structure
Thumb
Synonyms
  • Diacereína
External IDs
AC-201 / SF-277
Categories
UNII
4HU6J11EL5
CAS number
13739-02-1
Weight
Average: 368.297
Monoisotopic: 368.053217346
Chemical Formula
C19H12O8
InChI Key
TYNLGDBUJLVSMA-UHFFFAOYSA-N
InChI
InChI=1S/C19H12O8/c1-8(20)26-13-5-3-4-11-15(13)18(23)16-12(17(11)22)6-10(19(24)25)7-14(16)27-9(2)21/h3-7H,1-2H3,(H,24,25)
IUPAC Name
4,5-bis(acetyloxy)-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid
SMILES
CC(=O)OC1=CC=CC2=C1C(=O)C1=C(OC(C)=O)C=C(C=C1C2=O)C(O)=O

Pharmacology

Indication

For the treatment of osteoarthritis affecting the hip or knee 6.

Pharmacodynamics

Decreases inflammation and cartilage destruction and also corrects altered osteoblast acitivity 3 4 5.

Mechanism of action

Diacerein's active metabolite rhein Rhein reduces cartilage destruction by decreasing expression of matrix metalloproteinase (MMP)-1 and -3 as well as upregulating tissue inhibitor of matrix metalloproteinases which serve to reduce the activity of several MMPs 5. The anti-inflammatory action of rhein reduces the level of interleukin-1beta activity which plays a large role in reduction of extracellular matrix production, MMP activity, and continued inflammation 4. Rhein reduces abnormal osteoblast synthetic activity through an unknown mechanism 3.

TargetActionsOrganism
UOxysterols receptor LXR-alpha
inhibitor
Humans
UOxysterols receptor LXR-beta
inhibitor
Humans
UArylamine N-acetyltransferase (Helicobacter pylori)
inhibitor
Helicobacter pylori
UArachidonate 5-lipoxygenase
inhibitor
Humans
UCytochrome P450 1A2
inhibitor
Humans
UCYP3A
inhibitor
Humans
UCytochrome P450 2E1
inhibitor
Humans
UCytochrome P450 2C9
inhibitor
Humans
UCytochrome P450 2D6
inhibitor
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

Bioavailability of 50-60% 1. Entirely converted to the active metabolite rhein Rhein before reaching systemic circulation.

Volume of distribution

15-60L 1.

Protein binding

99% of rhein is bound to plasma proteins 1.

Metabolism

Entirely converted to rhien Rhein through double deacetylation before reaching systemic circulation 1. Rhein Rhein is further metabolized to rhein glucuronide and rhein sulfate.

Route of elimination

37% excreted in urine and 53% in feces as estimated in rats 2.

Half life

4-10h 1.

Clearance

Total CL is 1.5L/h and renal CL is 0.1L/h 1.

Toxicity

Rhein Rhein has an oral LD50 of >5000mg/kg in mice. This is equivalent to a diacerein dose of >6476mg/kg.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Diacerein.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Diacerein.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Diacerein.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Diacerein.
8-azaguanineThe metabolism of 8-azaguanine can be decreased when combined with Diacerein.
8-chlorotheophyllineThe metabolism of 8-chlorotheophylline can be decreased when combined with Diacerein.
9-DeazaguanineThe metabolism of 9-Deazaguanine can be decreased when combined with Diacerein.
9-MethylguanineThe metabolism of 9-Methylguanine can be decreased when combined with Diacerein.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Diacerein.
AceclofenacThe metabolism of Aceclofenac can be decreased when combined with Diacerein.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Evidence Level

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

References

General References
  1. Nicolas P, Tod M, Padoin C, Petitjean O: Clinical pharmacokinetics of diacerein. Clin Pharmacokinet. 1998 Nov;35(5):347-59. [PubMed:9839088]
  2. De Witte P, Lemli J: Excretion and distribution of [14C]rhein and [14C]rhein anthrone in rat. J Pharm Pharmacol. 1988 Sep;40(9):652-5. [PubMed:2907037]
  3. Pelletier JP, Lajeunesse D, Reboul P, Mineau F, Fernandes JC, Sabouret P, Martel-Pelletier J: Diacerein reduces the excess synthesis of bone remodeling factors by human osteoblast cells from osteoarthritic subchondral bone. J Rheumatol. 2001 Apr;28(4):814-24. [PubMed:11327257]
  4. Moldovan F, Pelletier JP, Jolicoeur FC, Cloutier JM, Martel-Pelletier J: Diacerhein and rhein reduce the ICE-induced IL-1beta and IL-18 activation in human osteoarthritic cartilage. Osteoarthritis Cartilage. 2000 May;8(3):186-96. [PubMed:10806046]
  5. Tamura T, Kosaka N, Ishiwa J, Sato T, Nagase H, Ito A: Rhein, an active metabolite of diacerein, down-regulates the production of pro-matrix metalloproteinases-1, -3, -9 and -13 and up-regulates the production of tissue inhibitor of metalloproteinase-1 in cultured rabbit articular chondrocytes. Osteoarthritis Cartilage. 2001 Apr;9(3):257-63. [PubMed:11300749]
  6. WHO Diacerein: Restricted Use [Link]
External Links
PubChem Compound
26248
PubChem Substance
347828314
ChemSpider
24456
BindingDB
32018
ChEBI
94708
ChEMBL
CHEMBL41286
Wikipedia
Diacerein
ATC Codes
M01AX21 — Diacerein
MSDS
Download (25.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedPreventionGout Flares1
2CompletedTreatmentAcute Gouty Arthritis1
2CompletedTreatmentBMI >27 kg/m2 / BMI >30 kg/m2 / Type 2 Diabetes Mellitus1
2CompletedTreatmentComplications of Diabetes Mellitus / Diabetes Mellitus (DM) / Type 2 Diabetes Mellitus1
2CompletedTreatmentRheumatoid Arthritis1
2CompletedTreatmentType 2 Diabetes Mellitus1
2Enrolling by InvitationTreatmentEpidermolysis Bullosa Simplex1
2Not Yet RecruitingTreatmentThrombocytopenias1
2RecruitingTreatmentDiabetes-Related Complications / Insulin Resistance / Type 2 Diabetes Mellitus1
3Active Not RecruitingTreatmentKnee Osteoarthritis (Knee OA) / Osteoarthritis (OA)1
3CompletedTreatmentNon-Alcoholic Fatty Liver Disease (NAFLD) / Type 2 Diabetes Mellitus1
3CompletedTreatmentOsteoarthritis, Hip1
4CompletedTreatmentDiacerein / Glucosamine / Osteoarthritis (OA)1
4CompletedTreatmentKnee Osteoarthritis (Knee OA)1
4CompletedTreatmentKnee Osteoarthritis (Knee OA) / Osteoarthritis (OA)1
4CompletedTreatmentOsteoarthritis (OA)1
4CompletedTreatmentPrimary Gout1
4RecruitingTreatmentKnee Osteoarthritis (Knee OA)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0407 mg/mLALOGPS
logP2.14ALOGPS
logP1.79ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)3.37ChemAxon
pKa (Strongest Basic)-6.8ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area124.04 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity90.67 m3·mol-1ChemAxon
Polarizability35.37 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as anthracenecarboxylic acids. These are organic compounds containing a carboxylic acid group attached to an anthracene ring system.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Anthracenes
Sub Class
Anthracenecarboxylic acids and derivatives
Direct Parent
Anthracenecarboxylic acids
Alternative Parents
Anthraquinones / Naphthalenecarboxylic acids / Tricarboxylic acids and derivatives / Aryl ketones / Carboxylic acid esters / Carboxylic acids / Organic oxides / Hydrocarbon derivatives
Substituents
Anthracene carboxylic acid / 9,10-anthraquinone / Anthraquinone / 2-naphthalenecarboxylic acid / 2-naphthalenecarboxylic acid or derivatives / Tricarboxylic acid or derivatives / Aryl ketone / Carboxylic acid ester / Ketone / Carboxylic acid
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Nuclear receptor. Interaction with RXR shifts RXR from its role as a silent DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by L...
Gene Name
NR1H3
Uniprot ID
Q13133
Uniprot Name
Oxysterols receptor LXR-alpha
Molecular Weight
50395.34 Da
References
  1. Sheng X, Zhu X, Zhang Y, Cui G, Peng L, Lu X, Zang YQ: Rhein protects against obesity and related metabolic disorders through liver X receptor-mediated uncoupling protein 1 upregulation in brown adipose tissue. Int J Biol Sci. 2012;8(10):1375-84. doi: 10.7150/ijbs.4575. Epub 2012 Oct 29. [PubMed:23139635]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Nuclear receptor. Binds preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence 5'-AGGTCA-3' and 4-nt spacing (DR-4). Regulates cholesterol uptake t...
Gene Name
NR1H2
Uniprot ID
P55055
Uniprot Name
Oxysterols receptor LXR-beta
Molecular Weight
50973.375 Da
References
  1. Sheng X, Zhu X, Zhang Y, Cui G, Peng L, Lu X, Zang YQ: Rhein protects against obesity and related metabolic disorders through liver X receptor-mediated uncoupling protein 1 upregulation in brown adipose tissue. Int J Biol Sci. 2012;8(10):1375-84. doi: 10.7150/ijbs.4575. Epub 2012 Oct 29. [PubMed:23139635]
3. Arylamine N-acetyltransferase (Helicobacter pylori)
Kind
Protein
Organism
Helicobacter pylori
Pharmacological action
Unknown
Actions
Inhibitor
References
  1. Chung JG, Tsou MF, Wang HH, Lo HH, Hsieh SE, Yen YS, Wu LT, Chang SH, Ho CC, Hung CF: Rhein affects arylamine N-acetyltransferase activity in Helicobacter pylori from peptic ulcer patients. J Appl Toxicol. 1998 Mar-Apr;18(2):117-23. [PubMed:9570694]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Iron ion binding
Specific Function
Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes.
Gene Name
ALOX5
Uniprot ID
P09917
Uniprot Name
Arachidonate 5-lipoxygenase
Molecular Weight
77982.595 Da
References
  1. Singh B, Nadkarni JR, Vishwakarma RA, Bharate SB, Nivsarkar M, Anandjiwala S: The hydroalcoholic extract of Cassia alata (Linn.) leaves and its major compound rhein exhibits antiallergic activity via mast cell stabilization and lipoxygenase inhibition. J Ethnopharmacol. 2012 May 7;141(1):469-73. doi: 10.1016/j.jep.2012.03.012. Epub 2012 Mar 17. [PubMed:22449441]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Tang JC, Yang H, Song XY, Song XH, Yan SL, Shao JQ, Zhang TL, Zhang JN: Inhibition of cytochrome P450 enzymes by rhein in rat liver microsomes. Phytother Res. 2009 Feb;23(2):159-64. doi: 10.1002/ptr.2572. [PubMed:18814214]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:
References
  1. Tang JC, Yang H, Song XY, Song XH, Yan SL, Shao JQ, Zhang TL, Zhang JN: Inhibition of cytochrome P450 enzymes by rhein in rat liver microsomes. Phytother Res. 2009 Feb;23(2):159-64. doi: 10.1002/ptr.2572. [PubMed:18814214]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Tang JC, Yang H, Song XY, Song XH, Yan SL, Shao JQ, Zhang TL, Zhang JN: Inhibition of cytochrome P450 enzymes by rhein in rat liver microsomes. Phytother Res. 2009 Feb;23(2):159-64. doi: 10.1002/ptr.2572. [PubMed:18814214]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Tang JC, Yang H, Song XY, Song XH, Yan SL, Shao JQ, Zhang TL, Zhang JN: Inhibition of cytochrome P450 enzymes by rhein in rat liver microsomes. Phytother Res. 2009 Feb;23(2):159-64. doi: 10.1002/ptr.2572. [PubMed:18814214]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Tang JC, Yang H, Song XY, Song XH, Yan SL, Shao JQ, Zhang TL, Zhang JN: Inhibition of cytochrome P450 enzymes by rhein in rat liver microsomes. Phytother Res. 2009 Feb;23(2):159-64. doi: 10.1002/ptr.2572. [PubMed:18814214]

Drug created on October 20, 2016 15:09 / Updated on May 01, 2019 11:20