Siponimod

Details

Stereochemistry	ACHIRAL
Molecular Formula	C29H35F3N2O3
Molecular Weight	516.595
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC1=CC(=CC=C1CN2CC(C2)C(O)=O)C(\C)=N\OCC3=CC=C(C4CCCCC4)C(=C3)C(F)(F)F

InChI

InChIKey=KIHYPELVXPAIDH-HNSNBQBZSA-N

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+

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26856814 | https://www.novartis.com/news/media-releases/novartis-announces-positive-phase-iii-results-showing-efficacy-baf312-patients

Siponimod (BAF312) is a dual agonist at the sphingosine-1 phosphate receptors, S1PR1 and S1PR5. The S1P receptor is commonly found on the surface of specific cells residing in the central nervous system (CNS), that are responsible for causing CNS damage that drives loss of function in secondary progressive multiple sclerosis (SPMS). Siponimod (BAF312) enters the brain and by binding to these specific receptors, may prevent the activation of these harmful cells, helping to reduce the loss of physical and cognitive function associated with SPMS.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Sphingosine 1-phosphate receptor Edg-1 12 Target ID: CHEMBL4333 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22646698	Agonist 2678	0.39 nM [EC50]
Sphingosine 1-phosphate receptor Edg-8 9 Target ID: CHEMBL2274 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22646698	Agonist 2678	0.98 nM [EC50]
Sphingosine 1-phosphate receptor Edg-6 9 Target ID: CHEMBL3230 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22646698	Agonist 2678	750.0 nM [EC50]

Conditions

Condition	Modality	Highest Phase	Product
Secondary progressive multiple sclerosis 5 Sources: https://clinicaltrials.gov/ct2/show/study/NCT01665144	Palliative	Phase III 656	SIPONIMOD Approved Use Unknown
Relapsing-remitting multiple sclerosis 10 Sources: https://clinicaltrials.gov/ct2/show/NCT00879658	Palliative	Phase II 1132	SIPONIMOD Approved Use Unknown
Active dermatomyositis 3 Sources: https://clinicaltrials.gov/ct2/show/record/NCT02029274	Palliative	Phase II 1132	SIPONIMOD Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
30.4 ng/mL EXPERIMENT https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf	2 mg 1 times / day steady-state, oral dose: 2 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		SIPONIMOD plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
558 ng × h/mL EXPERIMENT https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf	2 mg 1 times / day steady-state, oral dose: 2 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		SIPONIMOD plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
30 h EXPERIMENT https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf	2 mg 1 times / day steady-state, oral dose: 2 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		SIPONIMOD plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1 mg single, intravenous Dose: 1 mg Route: intravenous Route: single Dose: 1 mg Sources: https://pubmed.ncbi.nlm.nih.gov/31926605	healthy, 18-50 years n = 17 Health Status: healthy Age Group: 18-50 years Population Size: 17 Sources: https://pubmed.ncbi.nlm.nih.gov/31926605	Other AEs: Feeling hot, Dizziness... Other AEs: Feeling hot (5.9%) Dizziness (5.9%) Headache (5.9%) Presyncope (5.9%) Blurred vision (5.9%) Dry lips (5.9%) Nasopharyngitis (5.9%) Vaginal discharge (5.9%) Sources: https://pubmed.ncbi.nlm.nih.gov/31926605
2 mg 1 times / day steady, oral Recommended Dose: 2 mg, 1 times / day Route: oral Route: steady Dose: 2 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf	unhealthy, 49.0 years n = 1148 Health Status: unhealthy Condition: secondary progressive multiple sclerosis Age Group: 49.0 years Sex: M+F Population Size: 1148 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf	Disc. AE: Headache, Transaminases increased... AEs leading to discontinuation/dose reduction: Headache (0.1%) Transaminases increased (0.9%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf
2 mg 1 times / day steady, oral Recommended Dose: 2 mg, 1 times / day Route: oral Route: steady Dose: 2 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf	unhealthy, 49.0 years n = 1148 Health Status: unhealthy Condition: secondary progressive multiple sclerosis Age Group: 49.0 years Sex: M+F Population Size: 1148 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf	Disc. AE: Hypertension... AEs leading to discontinuation/dose reduction: Hypertension (10%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf
2 mg 1 times / day steady, oral Recommended Dose: 2 mg, 1 times / day Route: oral Route: steady Dose: 2 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 109	unhealthy, 49.0 years n = 1148 Health Status: unhealthy Condition: secondary progressive multiple sclerosis Age Group: 49.0 years Sex: M+F Population Size: 1148 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 109	Disc. AE: Macular edema, ALT increased... AEs leading to discontinuation/dose reduction: Macular edema (1%) ALT increased (0.5%) Bradycardia (0.3%) GGT increased (0.3%) AST increased (0.3%) Depression (0.3%) Dizziness (0.3%) Fatigue (0.3%) Pulmonary function test decreased (0.3%) Angina pectoris (0.2%) Edema peripheral (0.2%) Seminoma (0.2%) Uveitis (0.2%) Lymphopenia (0.1%) Urinary tract infection (0.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 109
20 mg 1 times / day multiple, oral Highest studied dose Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 38	healthy, adult Health Status: healthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 38	Other AEs: Headache, Dizziness... Other AEs: Headache (20.8%) Dizziness (5.7%) Nausea (4.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 38
75 mg single, oral Highest studied dose Dose: 75 mg Route: oral Route: single Dose: 75 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 38	healthy, adult Health Status: healthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 38	Other AEs: Headache, Dizziness... Other AEs: Headache (32%) Dizziness (12.1%) Nausea (5.5%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 38
10 mg 1 times / day multiple, oral Dose: 10 mg, 1 times / day Route: oral Route: multiple Dose: 10 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 109	unhealthy, adult n = 50 Health Status: unhealthy Age Group: adult Population Size: 50 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 109	Disc. AE: Macular edema, ALT increased... AEs leading to discontinuation/dose reduction: Macular edema (2%) ALT increased (2%) ALT increased (2%) AST increased (2%) Dizziness (4%) Edema peripheral (2%) Headache (2%) Lymphopenia (4%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf Page: p. 109

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	substrate 1037 inhibitor 1767 inducer 389	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2A6 707 CYP2C8 911 CYP2C19 1478 CYP2E1 882 BCRP 699 P-gp 1461 BSEP 402 MRP2 383 OAT1 599 OAT3 642 OCT1 512 OCT2 647 MATE1 306 MATE2 263	P-gp 1537 BCRP 561 MRP2 205	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=58 Page: 58.0	unlikely [IC50 >100 uM]
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=58 Page: 58.0	unlikely [IC50 >100 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=58 Page: 58.0	unlikely [IC50 >200 uM]
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=58 Page: 58.0	unlikely [IC50 >200 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=58 Page: 58.0	unlikely [IC50 >200 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=58 Page: 58.0	unlikely [IC50 >200 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=74 Page: 11,74	unlikely
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=74 Page: 11,74	unlikely
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=60 Page: 60.0	unlikely
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=60 Page: 60.0	unlikely
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=60 Page: 60.0	unlikely
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=60 Page: 60.0	unlikely
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=78 Page: 11,78	unlikely
MATE2 263	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=78 Page: 11,78	unlikely
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=74 Page: 11,74	unlikely
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=78 Page: 11,78	unlikely
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=78 Page: 11,78	unlikely
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=78 Page: 11,78	unlikely
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=78 Page: 11,78	unlikely
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=74 Page: 11,74	unlikely
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=58 Page: 58.0	weak [IC50 100 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=58 Page: 58.0	weak [IC50 230 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=11 Page: 11.0	no
MRP2 205	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=11 Page: 11.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#page=11 Page: 11.0	no
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209884s002lbl.pdf#page=16 Page: 16.0	yes	yes (co-administration study) Comment: administered with fluconazole (moderate CYP2C9 and CYP3A4 dual inhibitor): increased siponimod’s Cmax by 10% and the AUC 2-fold; administered with rifampin (strong CYP3A4 and moderate CYP2C9 dual inducer) decreased siponimod AUCtau,ss and Cmax,ss by 57% and 45%, respectively. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209884s002lbl.pdf#page=16 Page: 16.0
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209884s002lbl.pdf#page=16; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#PAGE=15 Page: 16.0	yes	yes (pharmacogenomic study) Comment: administered with fluconazole (moderate CYP2C9 and CYP3A4 dual inhibitor): increased siponimod’s Cmax by 10% and the AUC 2-fold; administered with rifampin (strong CYP3A4 and moderate CYP2C9 dual inducer) decreased siponimod AUCtau,ss and Cmax,ss by 57% and 45%, respectively. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209884s002lbl.pdf#page=16; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000ClinPharmR.pdf#PAGE=15 Page: 16.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000PharmR.pdf#page=23 Page: 23.0

Sourcing

Vendor/Aggregator	ID	URL
Excenen	EX-A873
Molcore	MC445558
Toronto Research Chemicals	S683660
ZINC	ZINC000138611691	http://zinc15.docking.org/substances/ZINC000138611691
mcule	MCULE-4593242052

PubMed

Title	Date	PubMed
The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P₁) and hypertension (S1P₃) in rat.	2012	23285242
The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate.	2012 Nov	22646698
Circulating monocytes are reduced by sphingosine-1-phosphate receptor modulators independently of S1P3.	2013 Apr 1	23436932
Modulators of the Sphingosine 1-phosphate receptor 1.	2013 Dec 1	24125884
Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator.	2013 Mar 14	24900670
Sphingosine 1-phosphate receptor modulators in multiple sclerosis.	2015 Jul	26239599
Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis.	2016 Aug 26	27566665
The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures.	2016 Feb 8	26856814

Patents

Sample Use Guides

In Vivo Use Guide

Patients received 2 mg once daily siponimod (following initial dose titration starting at 0.25 mg).

Route of Administration: Oral

In Vitro Use Guide

The selectivity of siponimod (BAF312) for receptor subtypes S1P1 and S1P5, sparing activity on the S1P2, S1P3 and S1P4 receptors, was demonstrated by measuring agonist efficacy in the GTPγ[35S] binding assay. The half-maximal effective concentration (EC50) values were in the sub-nanomolar range for S1P1 (0.39 ± 0.07 nM) and S1P5 (0.98 ± 0.43 nM) receptors, with Emax levels of approximately 100% (full agonist).

Name

Type

Language

Siponimod

Official Name

English

1-[[4-[(1E)-1-[[[4-Cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino]ethyl]-2-ethylphenyl]methyl]-3-azetidinecarboxylic acid

Systematic Name

English

3-Azetidinecarboxylic acid, 1-[[4-[(1E)-1-[[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino]ethyl]-2-ethylphenyl]methyl]-

Systematic Name

English

siponimod [INN]

Common Name

English

NVP-BAF312-NX

Code

English

Siponimod [WHO-DD]

Common Name

English

BAF312

Code

English

BAF-312

Code

English

SIPONIMOD [USAN]

Common Name

English

SIPONIMOD [MI]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

437614