Ozanimod

Identification

Summary

Ozanimod is a sphingosine 1-phosphate receptor modulator being studied to treat Multiple Sclerosis (MS) and inflammatory bowel disease (IBD).

Brand Names
Zeposia, Zeposia 7-day Starter Pack, Zeposia Starter Kit
Generic Name
Ozanimod
DrugBank Accession Number
DB12612
Background

Ozanimod is a once-daily sphingosine 1-phosphate receptor modulator for the treatment of relapsing Multiple Sclerosis (MS) and inflammatory bowel disease. It was developed by Celgene (now acquired by Bristol-Myers Squibb) 9 and was approved by the FDA on March 26, 2020.10,11 The US approval was followed by the approval in Canada on October 2, 2020.14 In November 2021, ozanimod was also approved by the European Commission for the treatment of adults with relapsing remitting multiple sclerosis.12,13

MS is a devastating inflammatory disease that often progresses and causes severe neurological, physical, and cognitive effects.4 Inflammatory bowel disease also a chronic inflammatory condition and can cause persistent abdominal pain, diarrhea, bloody stools, and vomiting.5

In clinical trials, Ozanimod has been shown to be well-tolerated and has resulted in a higher decrease in the rate of MS relapses than with intramuscular interferon beta-1a, a current standard in MS therapy. Studies involving patients with inflammatory bowel disease have also shown promising results.1,6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 404.47
Monoisotopic: 404.184840649
Chemical Formula
C23H24N4O3
Synonyms
  • Ozanimod
  • Ozanimodum
External IDs
  • RPC 1063
  • RPC-1063
  • RPC1063

Pharmacology

Indication

Ozanimod is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. It is also used to treat moderately to severely active ulcerative colitis (UC) in adults.11,13,14

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofClinically isolated syndrome (cis)•••••••••••••••••••
Management ofModerately to severely active ulcerative colitis••••••••••••••••••••••••••• •••••••• •• •••••••••••• ••••••••••••••
Management ofModerately to severely active ulcerative colitis••••••••••••••••••••••••
Treatment ofProgressive multiple sclerosis (pms)•••••••••••••••••••
Management ofRelapsing forms of multiple sclerosis••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Ozanimod reduces circulating lymphocytes that cause the neuroinflammation associated with MS, reducing debilitating symptoms and, possibly, disease progression. During clinical trials, ozanimod reduced MS-associated brain volume loss in several regions.1,11 Ozanimod causes the sequestration of peripheral lymphocytes, reducing circulating lymphocytes in the gastrointestinal tract.7

Mechanism of action

Sphingosine‐1‐phosphate (S1P) is an important phospholipid that binds to various G‐protein‐coupled receptor subtypes, which can be identified as S1P1–5R. S1P and the receptors it binds to perform regular functions in the immune, cardiovascular, pulmonary, and nervous system.2,7 S1P can be expressed ubiquitously, playing an important role in regulating inflammation. S1P1R, S1P2R, and S1P3R receptors can be found in the cardiovascular, immune, and central nervous systems. S1P4R is found on lymphocytic and hematopoietic cells, while S1P5R expression is found only on the spleen (on natural killer cells) or in the central nervous system.3

Ozanimod is a selective modulator of S1P receptors and binds to S1P1R and S1P5R subtypes.3 The mechanism of action of ozanimod is not fully understood, but this drug likely reduces the migration of lymphocytes that usually aggravate the inflammation associated with MS.11

TargetActionsOrganism
ASphingosine 1-phosphate receptor 1
agonist
Humans
ASphingosine 1-phosphate receptor 5
agonist
Humans
Absorption

Ozanimod is absorbed in the gastrointestinal tract after oral administration. The Cmax of ozanimod is 0.244 ng/mL11 and is achieved at 6 to 8 hours after administration7, reaching steady-state at about 102 hours after administration. The AUC is 4.46 ng*h/mL.11 Its delayed absorption reduces effects that may occur after the first dose, such as heart rate changes. The peak plasma concentration of ozanimod is low due to a high volume of distribution.7

Volume of distribution

The average volume of distribution of ozanimod is 5590L.11 Another reference mentions a volume of distribution ranging from 73-101 L/kg.2 This drug crosses the blood-brain barrier.7

Protein binding

The plasma protein binding of ozanimod and its metabolites exceeds 98%.11

Metabolism

Ozanimod has two major active metabolites CC112273 and CC1084037 and minor active metabolites such as RP101988, RP101075, and RP101509, which target the S1P1 and S1P5 receptors. The enzymes involved in the metabolism of ozanimod include ALDH/ADH, NAT-2, Monoamine Oxidase B, and AKR 1C1/1C2. After metabolism, ozanimod (6%), CC112273 (73%), and CC1084037 (15%) are accounted for in the circulation.11

Hover over products below to view reaction partners

Route of elimination

The kidneys are not a major source of elimination for ozanimod.2 After a 0.92 mg dose of radiolabeled ozanimod was administered, about 26% of the labeled drug was accounted for in the urine and 37 % in the feces, mainly in the form of inactive metabolites.11

Half-life

The half-life of ozanimod ranges from 17-21 hours.2,7,11

Clearance

The mean apparent oral clearance of ozanimod, according to prescribing information, is 192 L/h.11 Another reference indicates an oral clearance of 233 L/h.2

Adverse Effects
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Toxicity

Overdose and LD50 information for ozanimod is not readily available in the literature.2,8,11 The NOAEL dose is 0.164 mg/kg/d for monkeys, and the human equivalent dose to this is about 0.053 mg/kg/day.2 An overdose of this drug likely results in adverse effects such as somnolence, fatigue, headache, dizziness, bradyarrhythmia, cardiac conduction defects, hypertension, liver injury, and nausea.2,11

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Ozanimod.
AbemaciclibAbemaciclib may decrease the excretion rate of Ozanimod which could result in a higher serum level.
AbirateroneThe metabolism of Ozanimod can be decreased when combined with Abiraterone.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Ozanimod.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Ozanimod.
Food Interactions
  • Avoid tyramine-containing foods and supplements. Avoid food containing high amounts of tyramine (>150mg) as these may increase the risk of hypertension when taken with ozanimod.
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Ozanimod hydrochloride3UPR33JAAM1618636-37-5HAOOCAKHSFYDBU-BDQAORGHSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZeposiaCapsule0.92 mgOralBristol Myers Squibb Pharma Eeig2020-12-23Not applicableEU flag
ZeposiaCapsule0.92 mgOralBristol Myers Squibb Pharma Eeig2020-12-23Not applicableEU flag
ZeposiaCapsule0.92 mgOralBristol Myers Squibb2020-11-12Not applicableCanada flag
ZeposiaCapsule0.92 mg/1OralCelgene Corporation2020-03-27Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ZeposiaOzanimod (0.23 mg) + Ozanimod (0.46 mg)CapsuleOralBristol Myers Squibb Pharma Eeig2020-12-23Not applicableEU flag
ZEPOSIAOzanimod (0.46 MG) + Ozanimod (0.23 MG)Capsule; KitOralBristol Myers Squibb Pharma Eeig2020-12-05Not applicableItaly flag
ZeposiaOzanimod (0.23 mg) + Ozanimod (0.46 mg)CapsuleOralBristol Myers Squibb Pharma Eeig2020-12-23Not applicableEU flag
ZeposiaOzanimod hydrochloride (0.23 mg) + Ozanimod hydrochloride (0.46 mg)CapsuleOralBristol Myers Squibb2020-11-12Not applicableCanada flag
ZEPOSIAOzanimod (0.46 MG) + Ozanimod (0.23 MG)Capsule; KitOralBristol Myers Squibb Pharma Eeig2020-12-05Not applicableItaly flag

Categories

ATC Codes
L04AE02 — Ozanimod
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenyloxadiazoles. These are polycyclic aromatic compounds containing a benzene ring linked to a 1,2,4-oxadiazole ring through a CC or CN bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Oxadiazoles
Direct Parent
Phenyloxadiazoles
Alternative Parents
Indanes / Phenoxy compounds / Phenol ethers / Benzonitriles / Aralkylamines / Alkyl aryl ethers / Heteroaromatic compounds / 1,2-aminoalcohols / Oxacyclic compounds / Nitriles
show 5 more
Substituents
1,2-aminoalcohol / Alcohol / Alkanolamine / Alkyl aryl ether / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzonitrile
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
Z80293URPV
CAS number
1306760-87-1
InChI Key
XRVDGNKRPOAQTN-FQEVSTJZSA-N
InChI
InChI=1S/C23H24N4O3/c1-14(2)29-21-9-6-15(12-16(21)13-24)23-26-22(27-30-23)19-5-3-4-18-17(19)7-8-20(18)25-10-11-28/h3-6,9,12,14,20,25,28H,7-8,10-11H2,1-2H3/t20-/m0/s1
IUPAC Name
5-{3-[(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl]-1,2,4-oxadiazol-5-yl}-2-(propan-2-yloxy)benzonitrile
SMILES
CC(C)OC1=C(C=C(C=C1)C1=NC(=NO1)C1=C2CC[C@H](NCCO)C2=CC=C1)C#N

References

Synthesis Reference

Florian Uthoff, Jana Löwe, Christina Harms, Kai Donsbach, Harald Gröger. Chemoenzymatic Synthesis of a Chiral Ozanimod Key Intermediate Starting from Naphthalene as Cheap Petrochemical Feedstock. April 2019. The Journal of Organic Chemistry. DOI: 10.1021/acs.joc.8b03290

General References
  1. Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala Havrdova E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Huang V, Kappos L: Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019 Nov;18(11):1021-1033. doi: 10.1016/S1474-4422(19)30238-8. Epub 2019 Sep 3. [Article]
  2. Tran JQ, Hartung JP, Peach RJ, Boehm MF, Rosen H, Smith H, Brooks JL, Timony GA, Olson AD, Gujrathi S, Frohna PA: Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator. J Clin Pharmacol. 2017 Aug;57(8):988-996. doi: 10.1002/jcph.887. Epub 2017 Apr 11. [Article]
  3. Tran JQ, Hartung JP, Tompkins CA, Frohna PA: Effects of High- and Low-Fat Meals on the Pharmacokinetics of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator. Clin Pharmacol Drug Dev. 2018 Aug;7(6):634-640. doi: 10.1002/cpdd.409. Epub 2017 Nov 10. [Article]
  4. Ghasemi N, Razavi S, Nikzad E: Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017 Apr-Jun;19(1):1-10. Epub 2016 Dec 21. [Article]
  5. Fakhoury M, Negrulj R, Mooranian A, Al-Salami H: Inflammatory bowel disease: clinical aspects and treatments. J Inflamm Res. 2014 Jun 23;7:113-20. doi: 10.2147/JIR.S65979. eCollection 2014. [Article]
  6. Vetter M, Neurath MF: Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges. Therap Adv Gastroenterol. 2017 Oct;10(10):773-790. doi: 10.1177/1756283X17727388. Epub 2017 Sep 5. [Article]
  7. Chaudhry BZ, Cohen JA, Conway DS: Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis. Neurotherapeutics. 2017 Oct;14(4):859-873. doi: 10.1007/s13311-017-0565-4. [Article]
  8. Cohen JA, Comi G, Arnold DL, Bar-Or A, Selmaj KW, Steinman L, Havrdova EK, Cree BA, Montalban X, Hartung HP, Huang V, Frohna P, Skolnick BE, Kappos L: Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study. Mult Scler. 2019 Aug;25(9):1255-1262. doi: 10.1177/1352458518789884. Epub 2018 Jul 25. [Article]
  9. Celgene: Press releases archive [Link]
  10. AJMC: FDA approves Zeposia (Ozanimod) for patients with RMS [Link]
  11. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
  12. BioSpace News Release: Bristol Myers Squibb Receives European Commission Approval of Zeposia (ozanimod) for use in Adults with Moderately to Severely Active Ulcerative Colitis [Link]
  13. Summary of Product Characteristics: Zeposia (ozanimod) oral capsules [Link]
  14. Health Canada Approved Drug Products: ZEPOSIA (ozanimod) Oral Capsules [Link]
PubChem Compound
52938427
PubChem Substance
347828826
ChemSpider
34979946
BindingDB
50507186
RxNav
2288236
ChEMBL
CHEMBL3707247
ZINC
ZINC000116109867
PDBe Ligand
JEU
Wikipedia
Ozanimod
PDB Entries
7ew0
FDA label
Download (369 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableActive Not RecruitingNot AvailableMultiple Sclerosis1somestatusstop reasonjust information to hide
Not AvailableActive Not RecruitingNot AvailableUlcerative Colitis1somestatusstop reasonjust information to hide
Not AvailableCompletedNot AvailableHealthy Volunteers (HV)1somestatusstop reasonjust information to hide
Not AvailableEnrolling by InvitationNot AvailableAdherence, Medication / Multiple Sclerosis1somestatusstop reasonjust information to hide
Not AvailableNot Yet RecruitingNot AvailableUlcerative Colitis1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral
CapsuleOral0.92 mg
CapsuleOral0.92 mg/1
Capsule; kitOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8481573No2013-07-092029-05-14US flag
US9382217No2016-07-052029-05-14US flag
US8796318No2014-08-052029-05-14US flag
US10239846No2019-03-262030-11-15US flag
US11680050No2018-09-302038-09-30US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)134-137https://www.trc-canada.com/product-detail/?CatNum=O880000&__cf_chl_jschl_tk__=47418a3658c1bed2236975a78c4d009d9726aa64-1585324169-0-AVBdS0uIBZsziaubuiosHQ9SfMRbB8tzILtS_D8ROwXY3jfZIfe7nf68lYLXjCK3VPlPXWBy25ZsDzjuSRHMsq4i6AooTGfw__9JzT3wXrvVSSMU2EcrV7Mv40mnq3e2lIo4_w_bP6jZ3VXuonZ_xdQiH-fceyd07BbLIF4BZmVUCw323soeydBwwDrMkF8dmXn9dgJ2cvO1O9LQY8_gDfhGL3Es8UF5YZpSXPUJEPZZo2_oXA4uk-2QpHpCZeR5oZIdF_CMMX2z5--DAw52pjMVLVTwvoNQS0ux0IEnKEV-UYKTAUK2pG7eAUZl2Cjvrg
boiling point (°C)648.3±65.0https://www.chemsrc.com/en/cas/1306760-87-1_828967.html
logP3.73https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8709
pKa14.73±0.10https://www.chemicalbook.com/ChemicalProductProperty_EN_CB42716147.htm
Predicted Properties
PropertyValueSource
Water Solubility0.161 mg/mLALOGPS
logP2.81ALOGPS
logP3.96Chemaxon
logS-3.4ALOGPS
pKa (Strongest Acidic)15.6Chemaxon
pKa (Strongest Basic)8.96Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area104.2 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity135.66 m3·mol-1Chemaxon
Polarizability45.21 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
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/MSsplash10-0a4l-0009700000-bdc342ffe8062d9f9287
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-3006900000-bf3493a63bdf49c15697
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0gvk-0009100000-8bfa7507ca68d6aa8083
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0zfu-0019100000-ac4c8a20c56ca29be9a3
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0kuu-1329100000-0daa99421a74fcc461a2
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-057l-2109000000-9d508940832266e9dd13
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-196.34586
predicted
DeepCCS 1.0 (2019)
[M+H]+198.70387
predicted
DeepCCS 1.0 (2019)
[M+Na]+205.09543
predicted
DeepCCS 1.0 (2019)

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activation of RAC1, SRC, PTK2/FAK1 and MAP kinases. Plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase SPHK1. Required for normal chemotaxis toward sphingosine 1-phosphate. Required for normal embryonic heart development and normal cardiac morphogenesis. Plays an important role in the regulation of sprouting angiogenesis and vascular maturation. Inhibits sprouting angiogenesis to prevent excessive sprouting during blood vessel development. Required for normal egress of mature T-cells from the thymus into the blood stream and into peripheral lymphoid organs. Plays a role in the migration of osteoclast precursor cells, the regulation of bone mineralization and bone homeostasis (By similarity). Plays a role in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by pulmonary endothelial cells and in the protection against ventilator-induced lung injury
Specific Function
G protein-coupled receptor activity
Gene Name
S1PR1
Uniprot ID
P21453
Uniprot Name
Sphingosine 1-phosphate receptor 1
Molecular Weight
42810.195 Da
References
  1. Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala Havrdova E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Huang V, Kappos L: Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019 Nov;18(11):1021-1033. doi: 10.1016/S1474-4422(19)30238-8. Epub 2019 Sep 3. [Article]
  2. Tran JQ, Hartung JP, Peach RJ, Boehm MF, Rosen H, Smith H, Brooks JL, Timony GA, Olson AD, Gujrathi S, Frohna PA: Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator. J Clin Pharmacol. 2017 Aug;57(8):988-996. doi: 10.1002/jcph.887. Epub 2017 Apr 11. [Article]
  3. Tran JQ, Hartung JP, Tompkins CA, Frohna PA: Effects of High- and Low-Fat Meals on the Pharmacokinetics of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator. Clin Pharmacol Drug Dev. 2018 Aug;7(6):634-640. doi: 10.1002/cpdd.409. Epub 2017 Nov 10. [Article]
  4. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
  5. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. Is coupled to both the G(i/0)alpha and G(12) subclass of heteromeric G-proteins (By similarity). May play a regulatory role in the transformation of radial glial cells into astrocytes and may affect proliferative activity of these cells
Specific Function
G protein-coupled receptor activity
Gene Name
S1PR5
Uniprot ID
Q9H228
Uniprot Name
Sphingosine 1-phosphate receptor 5
Molecular Weight
41774.515 Da
References
  1. Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala Havrdova E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Huang V, Kappos L: Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019 Nov;18(11):1021-1033. doi: 10.1016/S1474-4422(19)30238-8. Epub 2019 Sep 3. [Article]
  2. Tran JQ, Hartung JP, Peach RJ, Boehm MF, Rosen H, Smith H, Brooks JL, Timony GA, Olson AD, Gujrathi S, Frohna PA: Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator. J Clin Pharmacol. 2017 Aug;57(8):988-996. doi: 10.1002/jcph.887. Epub 2017 Apr 11. [Article]
  3. Tran JQ, Hartung JP, Tompkins CA, Frohna PA: Effects of High- and Low-Fat Meals on the Pharmacokinetics of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator. Clin Pharmacol Drug Dev. 2018 Aug;7(6):634-640. doi: 10.1002/cpdd.409. Epub 2017 Nov 10. [Article]
  4. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Catalyzes the oxidation of medium and long chain aliphatic aldehydes to fatty acids. Active on a variety of saturated and unsaturated aliphatic aldehydes between 6 and 24 carbons in length (PubMed:18035827, PubMed:18182499, PubMed:22633490, PubMed:25047030, PubMed:9133646, PubMed:9662422). Responsible for conversion of the sphingosine 1-phosphate (S1P) degradation product hexadecenal to hexadecenoic acid (PubMed:22633490)
Specific Function
3-chloroallyl aldehyde dehydrogenase activity
Gene Name
ALDH3A2
Uniprot ID
P51648
Uniprot Name
Aldehyde dehydrogenase family 3 member A2
Molecular Weight
54847.36 Da
References
  1. Tran JQ, Hartung JP, Olson AD, Mendzelevski B, Timony GA, Boehm MF, Peach RJ, Gujrathi S, Frohna PA: Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study. Clin Pharmacol Drug Dev. 2018 Mar;7(3):263-276. doi: 10.1002/cpdd.383. Epub 2017 Aug 7. [Article]
  2. Rasche L, Paul F: Ozanimod for the treatment of relapsing remitting multiple sclerosis. Expert Opin Pharmacother. 2018 Dec;19(18):2073-2086. doi: 10.1080/14656566.2018.1540592. Epub 2018 Nov 8. [Article]
  3. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Catalyzes the oxidation of long-chain primary alcohols and the oxidation of S-(hydroxymethyl) glutathione (PubMed:8460164). Also oxidizes long chain omega-hydroxy fatty acids, such as 20-HETE, producing both the intermediate aldehyde, 20-oxoarachidonate and the end product, a dicarboxylic acid, (5Z,8Z,11Z,14Z)-eicosatetraenedioate (PubMed:16081420). Class-III ADH is remarkably ineffective in oxidizing ethanol (PubMed:8460164). Required for clearance of cellular formaldehyde, a cytotoxic and carcinogenic metabolite that induces DNA damage (PubMed:33355142). Also acts as a S-nitroso-glutathione reductase by catalyzing the NADH-dependent reduction of S-nitrosoglutathione, thereby regulating protein S-nitrosylation (By similarity)
Specific Function
alcohol dehydrogenase (NAD+) activity, zinc-dependent
Gene Name
ADH5
Uniprot ID
P11766
Uniprot Name
Alcohol dehydrogenase class-3
Molecular Weight
39723.945 Da
References
  1. Tran JQ, Hartung JP, Olson AD, Mendzelevski B, Timony GA, Boehm MF, Peach RJ, Gujrathi S, Frohna PA: Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study. Clin Pharmacol Drug Dev. 2018 Mar;7(3):263-276. doi: 10.1002/cpdd.383. Epub 2017 Aug 7. [Article]
  2. Rasche L, Paul F: Ozanimod for the treatment of relapsing remitting multiple sclerosis. Expert Opin Pharmacother. 2018 Dec;19(18):2073-2086. doi: 10.1080/14656566.2018.1540592. Epub 2018 Nov 8. [Article]
  3. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Catalyzes the N- or O-acetylation of various arylamine and heterocyclic amine substrates (PubMed:12222688, PubMed:7915226). Participates in the detoxification of a plethora of hydrazine and arylamine drugs, and is able to bioactivate several known carcinogens
Specific Function
arylamine N-acetyltransferase activity
Gene Name
NAT2
Uniprot ID
P11245
Uniprot Name
Arylamine N-acetyltransferase 2
Molecular Weight
33570.245 Da
References
  1. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
Specific Function
arachidonic acid epoxygenase activity
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Catalyzes the oxidative deamination of primary and some secondary amines such as neurotransmitters, and exogenous amines including the tertiary amine, neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with concomitant reduction of oxygen to hydrogen peroxide and participates in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues (PubMed:11049757, PubMed:11134050, PubMed:20493079, PubMed:8316221, PubMed:8665924). Preferentially degrades benzylamine and phenylethylamine (PubMed:11049757, PubMed:11134050, PubMed:20493079, PubMed:8316221, PubMed:8665924)
Specific Function
aliphatic amine oxidase activity
Gene Name
MAOB
Uniprot ID
P27338
Uniprot Name
Amine oxidase [flavin-containing] B
Molecular Weight
58762.475 Da
References
  1. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids (PubMed:19218247). Most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentrations of NADPH (PubMed:14672942). Displays a broad positional specificity acting on positions 3, 17 and 20 of steroids and regulates the metabolism of hormones like estrogens and androgens (PubMed:10998348). May also reduce conjugated steroids such as 5alpha-dihydrotestosterone sulfate (PubMed:19218247). Displays affinity for bile acids (PubMed:8486699)
Specific Function
17-alpha,20-alpha-dihydroxypregn-4-en-3-one dehydrogenase activity
Gene Name
AKR1C1
Uniprot ID
Q04828
Uniprot Name
Aldo-keto reductase family 1 member C1
Molecular Weight
36788.02 Da
References
  1. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids (PubMed:19218247). Most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentrations of NADPH (PubMed:14672942). Displays a broad positional specificity acting on positions 3, 17 and 20 of steroids and regulates the metabolism of hormones like estrogens and androgens (PubMed:10998348). Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha-DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol) (PubMed:15929998, PubMed:17034817, PubMed:17442338, PubMed:8573067). Also specifically able to produce 17beta-hydroxy-5alpha-androstan-3-one/5alphaDHT (PubMed:10998348). May also reduce conjugated steroids such as 5alpha-dihydrotestosterone sulfate (PubMed:19218247). Displays affinity for bile acids (PubMed:8486699)
Specific Function
aldose reductase (NADPH) activity
Gene Name
AKR1C2
Uniprot ID
P52895
Uniprot Name
Aldo-keto reductase family 1 member C2
Molecular Weight
36734.97 Da
References
  1. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Catalyzes the oxidative deamination of primary and some secondary amines such as neurotransmitters, and exogenous amines including the tertiary amine, neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with concomitant reduction of oxygen to hydrogen peroxide and participates in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues (PubMed:11049757, PubMed:11134050, PubMed:20493079, PubMed:8316221, PubMed:8665924). Preferentially degrades benzylamine and phenylethylamine (PubMed:11049757, PubMed:11134050, PubMed:20493079, PubMed:8316221, PubMed:8665924)
Specific Function
aliphatic amine oxidase activity
Gene Name
MAOB
Uniprot ID
P27338
Uniprot Name
Amine oxidase [flavin-containing] B
Molecular Weight
58762.475 Da
References
  1. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
Specific Function
ABC-type xenobiotic transporter activity
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
Broad substrate specificity ATP-binding cassette transporter ABCG2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Weak substrate
General Function
Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function
ABC-type xenobiotic transporter activity
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
ATP-dependent translocase ABCB1
Molecular Weight
141477.255 Da
References
  1. Tran JQ, Hartung JP, Olson AD, Mendzelevski B, Timony GA, Boehm MF, Peach RJ, Gujrathi S, Frohna PA: Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study. Clin Pharmacol Drug Dev. 2018 Mar;7(3):263-276. doi: 10.1002/cpdd.383. Epub 2017 Aug 7. [Article]
  2. FDA Approved Drug Products: Zeposia (ozanimod) oral capsules [Link]

Drug created at October 20, 2016 23:12 / Updated at June 01, 2023 18:05