Details of the Drug

General Information of Drug (ID: DM2R86O)

Drug Name

Siponimod

Synonyms

BAF312

Indication

Disease Entry	ICD 11	Status	REF
Multiple sclerosis	8A40	Approved	[1]
Hepatocellular carcinoma	2C12.02	Phase 3	[2]
Rheumatoid arthritis	FA20	Phase 2	[3], [4]

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 1

Molecular Weight (mw)

516.6

Topological Polar Surface Area (xlogp)

4.8

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

Chemical Identifiers

Formula: C29H35F3N2O3
IUPAC Name: 1-[[4-[(E)-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid
Canonical SMILES: CCC1=C(C=CC(=C1)/C(=N/OCC2=CC(=C(C=C2)C3CCCCC3)C(F)(F)F)/C)CN4CC(C4)C(=O)O
InChI: InChI=1S/C29H35F3N2O3/c1-3-21-14-23(10-11-24(21)15-34-16-25(17-34)28(35)36)19(2)33-37-18-20-9-12-26(22-7-5-4-6-8-22)27(13-20)29(30,31)32/h9-14,22,25H,3-8,15-18H2,1-2H3,(H,35,36)/b33-19+
InChIKey: KIHYPELVXPAIDH-HNSNBQBZSA-N

Cross-matching ID

PubChem CID: 44599207
CAS Number: 1230487-00-9
DrugBank ID: DB12371
TTD ID: D07FKQ
VARIDT ID: DR00743
INTEDE ID: DR1488
ACDINA ID: D01430

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Sphingosine-1 phosphate receptor (S1PR)	TT7BQRM	NOUNIPROTAC	Modulator	[1]
Sphingosine-1-phosphate receptor 1 (S1PR1)	TT9JZCK	S1PR1_HUMAN	Modulator	[1]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[5]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Substrate	[5]

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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This Drug

Molecular Expression Atlas of This Drug

ICD Disease Classification

08 Nervous system disease

Disease Class

ICD-11: 8A40 Multiple sclerosis

The Studied Tissue

Plasmacytoid dendritic cells

The Studied Disease

Multiple sclerosis [ICD-11:8A40]

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Cytochrome P450 2C9 (CYP2C9)	DME	CYP2C9	9.09E-01	-9.26E-02	-3.68E-01
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	9.85E-01	2.24E-02	7.33E-02

Molecular Expression Atlas (MEA)

MEA Detail

Jump to Detail Molecular Expression Atlas of This Drug

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as Siponimod

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Disease	REF
Ozanimod	DMT6AM2	Major	Additive immunosuppressive effects by the combination of Siponimod and Ozanimod.	Multiple sclerosis [8A40]	[31]
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Coadministration of a Drug Treating the Disease Different from Siponimod (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Remdesivir	DMBFZ6L	Moderate	Increased risk of hepatotoxicity by the combination of Siponimod and Remdesivir.	1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019]	[31]
Ivosidenib	DM8S6T7	Major	Increased risk of ventricular arrhythmias by the combination of Siponimod and Ivosidenib.	Acute myeloid leukaemia [2A60]	[31]
Oliceridine	DM6MDCF	Major	Increased risk of ventricular arrhythmias by the combination of Siponimod and Oliceridine.	Acute pain [MG31]	[31]
Levalbuterol	DM5YBO1	Moderate	Increased risk of prolong QT interval by the combination of Siponimod and Levalbuterol.	Asthma [CA23]	[32]
Troleandomycin	DMUZNIG	Major	Decreased metabolism of Siponimod caused by Troleandomycin mediated inhibition of CYP450 enzyme.	Bacterial infection [1A00-1C4Z]	[31]
Pexidartinib	DMS2J0Z	Major	Increased metabolism of Siponimod caused by Pexidartinib mediated induction of CYP450 enzyme.	Bone/articular cartilage neoplasm [2F7B]	[31]
Lisocabtagene maraleucel	DMP45ME	Major	Additive immunosuppressive effects by the combination of Siponimod and Lisocabtagene maraleucel.	Diffuse large B-cell lymphoma [2A81]	[31]
Axicabtagene ciloleucel	DMYHN59	Major	Additive immunosuppressive effects by the combination of Siponimod and Axicabtagene ciloleucel.	Diffuse large B-cell lymphoma [2A81]	[31]
Eslicarbazepine	DMZREFQ	Major	Increased metabolism of Siponimod caused by Eslicarbazepine mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[31]
Bay 80-6946	DMLOS5R	Major	Additive immunosuppressive effects by the combination of Siponimod and Bay 80-6946.	Follicular lymphoma [2A80]	[31]
Avapritinib	DMK2GZX	Major	Additive immunosuppressive effects by the combination of Siponimod and Avapritinib.	Gastrointestinal stromal tumour [2B5B]	[31]
177Lu-DOTATATE	DMT8GVU	Major	Additive immunosuppressive effects by the combination of Siponimod and 177Lu-DOTATATE.	Hepatitis virus infection [1E50-1E51]	[31]
Berotralstat	DMWA2DZ	Major	Decreased metabolism of Siponimod caused by Berotralstat mediated inhibition of CYP450 enzyme.	Innate/adaptive immunodeficiency [4A00]	[31]
Lurbinectedin	DMEFRTZ	Major	Additive immunosuppressive effects by the combination of Siponimod and Lurbinectedin.	Lung cancer [2C25]	[31]
Selpercatinib	DMZR15V	Major	Increased risk of ventricular arrhythmias by the combination of Siponimod and Selpercatinib.	Lung cancer [2C25]	[31]
Tisagenlecleucel	DMM9BJD	Major	Additive immunosuppressive effects by the combination of Siponimod and Tisagenlecleucel.	Mature B-cell lymphoma [2A85]	[31]
Belantamab mafodotin	DMBT3AI	Major	Additive immunosuppressive effects by the combination of Siponimod and Belantamab mafodotin.	Multiple myeloma [2A83]	[31]
Fedratinib	DM4ZBK6	Major	Decreased metabolism of Siponimod caused by Fedratinib mediated inhibition of CYP450 enzyme.	Myeloproliferative neoplasm [2A20]	[31]
Inebilizumab	DMI0RHA	Major	Additive immunosuppressive effects by the combination of Siponimod and Inebilizumab.	Nervous system paraneoplastic/autoimmune disorder [8E4A]	[31]
Macimorelin	DMQYJIR	Major	Increased risk of ventricular arrhythmias by the combination of Siponimod and Macimorelin.	Pituitary gland disorder [5A60-5A61]	[31]
Tildrakizumab	DMLW9HG	Major	Additive immunosuppressive effects by the combination of Siponimod and Tildrakizumab.	Psoriasis [EA90]	[31]
Risankizumab	DMM32GT	Major	Additive immunosuppressive effects by the combination of Siponimod and Risankizumab.	Psoriasis [EA90]	[31]
Upadacitinib	DM32B5U	Major	Additive immunosuppressive effects by the combination of Siponimod and Upadacitinib.	Rheumatoid arthritis [FA20]	[31]
Mogamulizumab	DMISH0Z	Major	Additive immunosuppressive effects by the combination of Siponimod and Mogamulizumab.	Sezary syndrome [2B02]	[31]
Voxelotor	DMCS6M5	Major	Decreased metabolism of Siponimod caused by Voxelotor mediated inhibition of CYP450 enzyme.	Sickle-cell disorder [3A51]	[31]
Larotrectinib	DM26CQR	Moderate	Decreased metabolism of Siponimod caused by Larotrectinib mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[31]
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⏷ Show the Full List of 26 DDI Information of This Drug

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Crospovidone	E00626	Not Available	Disintegrant
Ferric hydroxide oxide yellow	E00539	23320441	Colorant
Ferric oxide black	E00522	16211978	Colorant
Glyceryl behenate	E00481	5362585	Binding agent; Coating agent; Flavoring agent; Modified-release agent; Viscosity-controlling agent; lubricant
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Polyvinyl alcohol	E00666	Not Available	Coating agent; Emulsion stabilizing agent; Film/Membrane-forming agent
Soybean lecithin	E00637	Not Available	Other agent
Talc	E00520	16211421	Anticaking agent; Diluent; Glidant; lubricant
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Haematite red	E00236	14833	Colorant
Hydrophobic colloidal silica	E00285	24261	Anticaking agent; Emulsion stabilizing agent; Glidant; Suspending agent; Viscosity-controlling agent
Cellulose microcrystalline	E00698	Not Available	Adsorbent; Suspending agent; Diluent
Xanthan gum	E00694	Not Available	Bioadhesive material; Emulsifying agent; Gelling agent; Modified-release agent; Suspending agent; Viscosity-controlling agent
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⏷ Show the Full List of 13 Pharmaceutical Excipients of This Drug

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Siponimod 0.25mg tablet	0.25mg	Tablet	Oral
Siponimod 2mg tablet	2mg	Tablet	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
2	ClinicalTrials.gov (NCT01665144) Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND). U.S. National Institutes of Health.
3	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
4	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
5	Metabolism and disposition of siponimod, a novel selective S1P1/S1P5 agonist, in healthy volunteers and in vitro identification of human cytochrome P450 enzymes involved in its oxidative metabolism. Drug Metab Dispos. 2018 Jul;46(7):1001-1013.
6	Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
7	Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
8	Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
9	Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
10	Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
11	Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
12	Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
13	The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
14	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.
15	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.
16	Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
17	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.
18	Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
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	Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
25	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
26	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
27	Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis. CNS Drugs. 2015 Jul;29(7):565-75.
28	Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov. 2013 Sep;12(9):688-702.
29	Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2520-4.
30	ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile. PLoS One. 2014 Oct 27;9(10):e110819.
31	Cerner Multum, Inc. "Australian Product Information.".
32	Product Information. Arcapta Neohaler (indacaterol). Novartis Pharmaceuticals, East Hanover, NJ.