Identification

Name
Apremilast
Accession Number
DB05676
Type
Small Molecule
Groups
Approved, Investigational
Description

Apremilast is a novel, orally available small molecule inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4). It is indicated in the treatment of active psoriatic arthritis in adults (approved by the FDA in March 2014) and moderate to severe plaque psoriasis (approved by the FDA in September 2014). PDE-4 is a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase that is predominantly located in inflammatory cells. By inhibiting PDE-4, apremilast increases intracellular levels of cAMP and thereby inhibits the production of multiple proinflammatory mediators including PDE-4, TNF-alpha, interleukin-2 (IL-2), interferon-gamma, leukotrienes, and nitric oxide synthase. By targeting a central component of the inflammatory signaling cascade rather than a single inflammatory marker, PDE-4 inhibition may restore the homeostatic balance between pro- and anti-inflammatory signalling.

Structure
Thumb
Synonyms
  • Apremilast
  • Aprémilast
  • Apremilastum
  • N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
External IDs
CC 10004 / CC-10004 / CC10004
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OtezlaTablet, film coated30.0 mg/1OralCelgene2014-04-03Not applicableUs
OtezlaTablet30 mgOralCelgene2014-12-01Not applicableCanada
OtezlaTablet, film coated30 mgOralCelgene Europe Bv2015-01-15Not applicableEu
OtezlaTablet, film coated30 mgOralCelgene Europe Bv2015-01-15Not applicableEu
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
OtezlaApremilast (10.0 mg/1) + Apremilast (20.0 mg/1) + Apremilast (30.0 mg/1)KitOralCelgene2014-03-25Not applicableUs
OtezlaApremilast (10 mg) + Apremilast (20 mg) + Apremilast (30 mg)Kit; TabletOralCelgene2014-11-27Not applicableCanada
OtezlaApremilast (10.0 mg/1) + Apremilast (20.0 mg/1) + Apremilast (30.0 mg/1)KitOralCelgene2015-02-01Not applicableUs
OtezlaApremilast (10.0 mg/1) + Apremilast (20.0 mg/1) + Apremilast (30.0 mg/1)KitOralCelgene2014-03-25Not applicableUs
OtezlaApremilast (10 mg) + Apremilast (20 mg) + Apremilast (30 mg)Kit; TabletOralCelgene2014-11-27Not applicableCanada
OtezlaApremilast (10.0 mg/1) + Apremilast (20.0 mg/1) + Apremilast (30.0 mg/1)KitOralCelgene2015-02-01Not applicableUs
OtezlaApremilast (10.0 mg/1) + Apremilast (20.0 mg/1) + Apremilast (30.0 mg/1)KitOralCelgene2014-03-25Not applicableUs
OtezlaApremilast (10 mg) + Apremilast (20 mg) + Apremilast (30 mg)Kit; TabletOralCelgene2014-11-27Not applicableCanada
OtezlaApremilast (10.0 mg/1) + Apremilast (20.0 mg/1) + Apremilast (30.0 mg/1)KitOralCelgene2015-02-01Not applicableUs
Categories
UNII
UP7QBP99PN
CAS number
608141-41-9
Weight
Average: 460.5
Monoisotopic: 460.130422295
Chemical Formula
C22H24N2O7S
InChI Key
IMOZEMNVLZVGJZ-QGZVFWFLSA-N
InChI
InChI=1S/C22H24N2O7S/c1-5-31-19-11-14(9-10-18(19)30-3)17(12-32(4,28)29)24-21(26)15-7-6-8-16(23-13(2)25)20(15)22(24)27/h6-11,17H,5,12H2,1-4H3,(H,23,25)/t17-/m1/s1
IUPAC Name
N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}ethanimidic acid
SMILES
[H][C@](CS(C)(=O)=O)(N1C(=O)C2=C(C1=O)C(=CC=C2)N=C(C)O)C1=CC(OCC)=C(OC)C=C1

Pharmacology

Indication

Investigated for use/treatment in psoriasis and psoriatic disorders.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Apremilast is a novel, orally available small molecule inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4). PDE-4 is a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase that is predominantly located in inflammatory cells. By inhibiting PDE-4, apremilast increases intracellular levels of cAMP and thereby inhibits the production of multiple proinflammatory mediators including PDE-4, TNF-alpha, interleukin-2 (IL-2), interferon-gamma, leukotrienes, and nitric oxide synthase. By targeting a central component of the inflammatory signaling cascade rather than a single inflammatory marker, PDE-4 inhibition may restore the homeostatic balance between pro- and anti-inflammatory signalling.

TargetActionsOrganism
AcAMP-specific 3',5'-cyclic phosphodiesterase 4D
antagonist
Human
AcAMP-specific 3',5'-cyclic phosphodiesterase 4A
antagonist
Human
AcAMP-specific 3',5'-cyclic phosphodiesterase 4B
antagonist
Human
UTumor necrosis factorNot AvailableHuman
UInterleukin-2Not AvailableHuman
UInterferon gammaNot AvailableHuman
UNitric oxide synthase, endothelialNot AvailableHuman
Absorption

When taken orally, apremilast is absorbed with an absolute bioavailability of ~73%. Co-administration with food does not alter the extent of absorption.

Volume of distribution

Peak plasma concentrations (Cmax) occur at a median time (tmax) of ~2.5 hours.

Protein binding

68%.

Metabolism

Apremilast is metabolized via multiple pathways, including cytochrome (CYP) 3A4-mediated oxidative metabolism with subsequent glucuronidation, non-enzymatic hydrolysis, and non-CYP3A4-mediated metabolism. The unchanged drug accounts for 45% of circulating radioactivity and <7 % of excreted radioactivity. The main metabolite of apremilast is O-desmethyl apremilast glucuronide (M12), with nine other minor metabolites all with at least 50-fold less potency than apremilast in inhibiting PDE-4 and TNF-a.

Route of elimination

58% urine; 39% feces.

Half life

6-9 hours.

Clearance

10 L/hr.

Toxicity

DEPRESSION AND SUICIDE: Apremilast has been associated with increased depression and suicidal behaviour in patients. WEIGHT LOSS: Apremilast has been associated with weight decrease in patients.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(4R)-limoneneThe risk or severity of adverse effects can be increased when Apremilast is combined with (4R)-limonene.
16-BromoepiandrosteroneThe risk or severity of adverse effects can be increased when Apremilast is combined with 16-Bromoepiandrosterone.
19-norandrostenedioneThe risk or severity of adverse effects can be increased when Apremilast is combined with 19-norandrostenedione.
5-androstenedioneThe risk or severity of adverse effects can be increased when Apremilast is combined with 5-androstenedione.
AceclofenacThe risk or severity of adverse effects can be increased when Apremilast is combined with Aceclofenac.
AcemetacinThe risk or severity of adverse effects can be increased when Apremilast is combined with Acemetacin.
AcetaminophenAcetaminophen may decrease the excretion rate of Apremilast which could result in a higher serum level.
AcetazolamideThe metabolism of Apremilast can be decreased when combined with Acetazolamide.
Acetyl sulfisoxazoleThe metabolism of Apremilast can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Apremilast which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Khobzaoui M, Gutke HJ, Burnet M: CC-10004 . Curr Opin Investig Drugs. 2005 May;6(5):518-25. [PubMed:15912967]
  2. Molostvov G, Morris A, Rose P, Basu S, Muller G: The effects of selective cytokine inhibitory drugs (CC-10004 and CC-1088) on VEGF and IL-6 expression and apoptosis in myeloma and endothelial cell co-cultures. Br J Haematol. 2004 Feb;124(3):366-75. [PubMed:14717786]
  3. Abdulrahim H, Thistleton S, Adebajo AO, Shaw T, Edwards C, Wells A: Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis. Expert Opin Pharmacother. 2015 May;16(7):1099-108. doi: 10.1517/14656566.2015.1034107. Epub 2015 Apr 11. [PubMed:25864487]
  4. Hoffmann M, Kumar G, Schafer P, Cedzik D, Capone L, Fong KL, Gu Z, Heller D, Feng H, Surapaneni S, Laskin O, Wu A: Disposition, metabolism and mass balance of [(14)C]apremilast following oral administration. Xenobiotica. 2011 Dec;41(12):1063-75. doi: 10.3109/00498254.2011.604745. Epub 2011 Aug 23. [PubMed:21859393]
External Links
KEGG Drug
D08860
PubChem Compound
11561674
PubChem Substance
310264858
ChemSpider
9736448
BindingDB
50248919
ChEBI
78540
ChEMBL
CHEMBL514800
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Apremilast
ATC Codes
L04AA32 — Apremilast
AHFS Codes
  • 92:36.00 — Disease-modifying Antirheumatic Agents
FDA label
Download (179 KB)
MSDS
Download (104 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Not Yet RecruitingTreatmentRecurrent Aphthous Stomatitis1
1CompletedNot AvailableHealthy Volunteers5
1CompletedBasic ScienceHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentPharmacokinetics1
1, 2CompletedTreatmentDiscoid Lupus Erythematosus (DLE)1
1, 2RecruitingTreatmentPrurigo Nodularis1
1, 2TerminatedTreatmentUveitis1
2Active Not RecruitingTreatmentPsoriasis1
2Active Not RecruitingTreatmentUlcerative Colitis (UC)1
2Active Not RecruitingTreatmentVitiligo1
2CompletedOtherHidradenitis Suppurativa (HS)1
2CompletedTreatmentAnkylosing Spondylitis (AS)1
2CompletedTreatmentAtopic Dermatitis (AD) / Dermatitis, Allergic Contact1
2CompletedTreatmentBehcet's Syndrome1
2CompletedTreatmentChronic Prostatitis With Chronic Pelvic Pain Syndrome / Prostatitis1
2CompletedTreatmentDermatitis, Atopic Dermatitis1
2CompletedTreatmentErosive Osteoarthritis of the Hand1
2CompletedTreatmentHidradenitis Suppurativa (HS)1
2CompletedTreatmentPapulopustular Rosacea (PPR) / Rosacea Subtype 1 (Erythematotelangiectatic)1
2CompletedTreatmentPrurigo Nodularis1
2CompletedTreatmentPsoriasis2
2CompletedTreatmentPsoriasis Vulgaris (Plaque Psoriasis) / Psoriasis-Type Psoriasis1
2CompletedTreatmentPsoriasis / Psoriasis Arthropatica / Psoriatic Arthritis1
2CompletedTreatmentPsoriasis / Psoriasis Vulgaris (Plaque Psoriasis)1
2CompletedTreatmentPsoriatic Arthritis1
2CompletedTreatmentRheumatoid Arthritis1
2CompletedTreatmentVulvodynia1
2Not Yet RecruitingTreatmentFemale Genital Disease / Lichen Planus of Vulva1
2RecruitingOtherAlcohol Use Disorder (AUD)1
2RecruitingTreatmentDermatitis Eczema / Dermatitis, Eczematous / Nummular Dermatitis / Nummular Eczema1
2RecruitingTreatmentDermatomyositis, Adult Type1
2RecruitingTreatmentItching1
2RecruitingTreatmentPsoriasis Vulgaris (Plaque Psoriasis)1
2RecruitingTreatmentVitiligo1
2TerminatedTreatmentAcne1
2TerminatedTreatmentRheumatoid Arthritis1
2Unknown StatusTreatmentLichen Planus (LP)1
2WithdrawnTreatmentAcute Gouty Arthritis1
2WithdrawnTreatmentChronic Plaque Psoriasis1
2WithdrawnTreatmentRheumatoid Arthritis1
3Active Not RecruitingTreatmentAnkylosing Spondyloarthritis1
3Active Not RecruitingTreatmentBehcet's Syndrome1
3Active Not RecruitingTreatmentPsoriasis1
3CompletedTreatmentPsoriasis Vulgaris (Plaque Psoriasis)2
3CompletedTreatmentPsoriasis / Psoriatic Arthritis1
3CompletedTreatmentPsoriatic Arthritis5
3Not Yet RecruitingTreatmentArthritis; Psoriasis (Etiology)1
3Not Yet RecruitingTreatmentPsoriasis Vulgaris (Plaque Psoriasis)1
3RecruitingTreatmentPsoriasis2
4CompletedTreatmentPalmo-plantar Psoriasis1
4CompletedTreatmentParapsoriasis1
4CompletedTreatmentPsoriasis Vulgaris (Plaque Psoriasis)1
4Enrolling by InvitationTreatmentPsoriasis / Psoriasis Vulgaris (Plaque Psoriasis) / Psoriatic Nail1
4Not Yet RecruitingTreatmentPsoriasis of the scalp / Psoriasis Vulgaris (Plaque Psoriasis)1
4RecruitingTreatmentCardiovascular Disease (CVD) / Psoriasis1
4RecruitingTreatmentCentral Centrifugal Cicatricial Alopecia1
4RecruitingTreatmentFrontal Fibrosing Alopecia1
4RecruitingTreatmentPsoriasis3
4RecruitingTreatmentPsoriasis Vulgaris (Plaque Psoriasis)2
4WithdrawnTreatmentPsoriatic Arthritis1
Not AvailableActive Not RecruitingNot AvailablePsoriasis1
Not AvailableActive Not RecruitingNot AvailablePsoriatic Arthritis1
Not AvailableActive Not RecruitingTreatmentAlopecia Areata (AA)1
Not AvailableCompletedNot AvailableAtopic Dermatitis (AD)1
Not AvailableRecruitingNot AvailablePsoriasis / Psoriatic Arthritis2
Not AvailableRecruitingNot AvailablePsoriatic Arthritis1
Not AvailableTerminatedTreatmentDermatomyositis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
KitOral
Kit; tabletOral
TabletOral30 mg
Tablet, film coatedOral30 mg
Tablet, film coatedOral30.0 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8802717No2003-03-192023-03-19Us
US6962940No2003-03-192023-03-19Us
US6020358No1998-10-302018-10-30Us
US7208516No2003-03-192023-03-19Us
US7659302No2003-03-192023-03-19Us
US8455536No2003-03-192023-03-19Us
US9018243No2003-03-192023-03-19Us
US7427638No2004-11-172024-11-17Us
US7893101No2003-12-092023-12-09Us
US9872854No2014-05-292034-05-29Us
US9724330No2003-03-192023-03-19Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0503 mg/mLALOGPS
logP1.79ALOGPS
logP1.39ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)4.83ChemAxon
pKa (Strongest Basic)-0.25ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area122.57 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity119.85 m3·mol-1ChemAxon
Polarizability46.71 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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 phthalimides. These are aromatic heterocyclic compounds containing a 1,3-dioxoisoindoline moiety. They are imide derivatives of phthalic anhydrides.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Isoindoles and derivatives
Sub Class
Isoindolines
Direct Parent
Phthalimides
Alternative Parents
Isoindoles / N-acetylarylamines / Anisoles / Methoxybenzenes / Phenoxy compounds / Alkyl aryl ethers / N-substituted carboxylic acid imides / Sulfones / Vinylogous amides / Acetamides
show 6 more
Substituents
Phthalimide / Isoindole / N-acetylarylamine / Phenol ether / N-arylamide / Methoxybenzene / Phenoxy compound / Anisole / Alkyl aryl ether / Benzenoid
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic ether, sulfone, phthalimides, N-acetylarylamine (CHEBI:78540)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Ubiquitin protein ligase binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name
PDE4D
Uniprot ID
Q08499
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4D
Molecular Weight
91114.1 Da
References
  1. Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M: Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26. [PubMed:17352685]
  2. Abdulrahim H, Thistleton S, Adebajo AO, Shaw T, Edwards C, Wells A: Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis. Expert Opin Pharmacother. 2015 May;16(7):1099-108. doi: 10.1517/14656566.2015.1034107. Epub 2015 Apr 11. [PubMed:25864487]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Metal ion binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name
PDE4A
Uniprot ID
P27815
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4A
Molecular Weight
98142.155 Da
References
  1. Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M: Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26. [PubMed:17352685]
  2. Abdulrahim H, Thistleton S, Adebajo AO, Shaw T, Edwards C, Wells A: Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis. Expert Opin Pharmacother. 2015 May;16(7):1099-108. doi: 10.1517/14656566.2015.1034107. Epub 2015 Apr 11. [PubMed:25864487]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Metal ion binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging f...
Gene Name
PDE4B
Uniprot ID
Q07343
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4B
Molecular Weight
83342.695 Da
References
  1. Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M: Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26. [PubMed:17352685]
  2. Abdulrahim H, Thistleton S, Adebajo AO, Shaw T, Edwards C, Wells A: Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis. Expert Opin Pharmacother. 2015 May;16(7):1099-108. doi: 10.1517/14656566.2015.1034107. Epub 2015 Apr 11. [PubMed:25864487]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Tumor necrosis factor receptor binding
Specific Function
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct ac...
Gene Name
TNF
Uniprot ID
P01375
Uniprot Name
Tumor necrosis factor
Molecular Weight
25644.15 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Kinase activator activity
Specific Function
Produced by T-cells in response to antigenic or mitogenic stimulation, this protein is required for T-cell proliferation and other activities crucial to regulation of the immune response. Can stimu...
Gene Name
IL2
Uniprot ID
P60568
Uniprot Name
Interleukin-2
Molecular Weight
17627.52 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Interferon-gamma receptor binding
Specific Function
Produced by lymphocytes activated by specific antigens or mitogens. IFN-gamma, in addition to having antiviral activity, has important immunoregulatory functions. It is a potent activator of macrop...
Gene Name
IFNG
Uniprot ID
P01579
Uniprot Name
Interferon gamma
Molecular Weight
19348.165 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Tetrahydrobiopterin binding
Specific Function
Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induce...
Gene Name
NOS3
Uniprot ID
P29474
Uniprot Name
Nitric oxide synthase, endothelial
Molecular Weight
133287.62 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Hoffmann M, Kumar G, Schafer P, Cedzik D, Capone L, Fong KL, Gu Z, Heller D, Feng H, Surapaneni S, Laskin O, Wu A: Disposition, metabolism and mass balance of [(14)C]apremilast following oral administration. Xenobiotica. 2011 Dec;41(12):1063-75. doi: 10.3109/00498254.2011.604745. Epub 2011 Aug 23. [PubMed:21859393]

Drug created on November 18, 2007 11:26 / Updated on October 15, 2018 04:36