siponimod   Click here for help

GtoPdb Ligand ID: 9289

Synonyms: BAF-312 | BAF312 | compound 32 [PMID: 24900670] | Mayzent®
Approved drug PDB Ligand Immunopharmacology Ligand
siponimod is an approved drug (FDA (2019), EMA (2020))
Compound class: Synthetic organic
Comment: Pharmacologically, siponimod (BAF312) is a selective sphingosine-1-phosphate (S1P) receptor agonist, with some selectivity for the S1P1 and S1P5 receptor isoforms [8]. It is an orally active drug. Siponimod was developed by Novartis for secondary progressive multiple sclerosis (SPMS), originally as a back-up compound for fingolimod. Compared to fingolimod it has more favourable pharmacokinetics.
Novartis announced positive results from their Phase 3 EXPAND study (BAF312 versus placebo) in SPMS (August 2016- link to announcement here).
The SIPR signalling pathway is important in autoimmune biology.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 3
Hydrogen bond donors 1
Rotatable bonds 10
Topological polar surface area 62.13
Molecular weight 516.26
XLogP 8
No. Lipinski's rules broken 1
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Canonical SMILES CCc1cc(ccc1CN1CC(C1)C(=O)O)C(=NOCc1ccc(c(c1)C(F)(F)F)C1CCCCC1)C
Isomeric SMILES CCc1cc(ccc1CN1CC(C1)C(=O)O)/C(=N/OCc1ccc(c(c1)C(F)(F)F)C1CCCCC1)/C
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+
1. Gates E. (1998)
A complement to care.
Nurs Times, 94 (9): 55-7. [PMID:9735753]
2. Gentile A, Musella A, Bullitta S, Fresegna D, De Vito F, Fantozzi R, Piras E, Gargano F, Borsellino G, Battistini L et al.. (2016)
Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis.
J Neuroinflammation, 13 (1): 207. [PMID:27566665]
3. Gergely P, Nuesslein-Hildesheim B, Guerini D, Brinkmann V, Traebert M, Bruns C, Pan S, Gray NS, Hinterding K, Cooke NG et al.. (2012)
The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate.
Br J Pharmacol, 167 (5): 1035-47. [PMID:22646698]
4. Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, Peter van Marle S, Legangneux E, Borell H, James AD et al.. (2018)
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, 46 (7): 1001-1013. [PMID:29735753]
5. Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, Vermersch P, Arnold DL, Arnould S, Scherz T et al.. (2018)
Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.
Lancet, 391 (10127): 1263-1273. [PMID:29576505]
6. Lewis ND, Haxhinasto SA, Anderson SM, Stefanopoulos DE, Fogal SE, Adusumalli P, Desai SN, Patnaude LA, Lukas SM, Ryan KR et al.. (2013)
Circulating monocytes are reduced by sphingosine-1-phosphate receptor modulators independently of S1P3.
J Immunol, 190 (7): 3533-40. [PMID:23436932]
7. O'Sullivan C, Schubart A, Mir AK, Dev KK. (2016)
The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures.
J Neuroinflammation, 13: 31. [PMID:26856814]
8. Pan S, Gray NS, Gao W, Mi Y, Fan Y, Wang X, Tuntland T, Che J, Lefebvre S, Chen Y et al.. (2013)
Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator.
ACS Med Chem Lett, 4 (3): 333-7. [PMID:24900670]
9. Shimano K, Maeda Y, Kataoka H, Murase M, Mochizuki S, Utsumi H, Oshita K, Sugahara K. (2019)
Amiselimod (MT-1303), a novel sphingosine 1-phosphate receptor-1 functional antagonist, inhibits progress of chronic colitis induced by transfer of CD4+CD45RBhigh T cells.
PLoS One, 14 (12): e0226154. [PMID:31805144]
10. Subei AM, Cohen JA. (2015)
Sphingosine 1-phosphate receptor modulators in multiple sclerosis.
CNS Drugs, 29 (7): 565-75. [PMID:26239599]
11. Urbano M, Guerrero M, Rosen H, Roberts E. (2013)
Modulators of the Sphingosine 1-phosphate receptor 1.
Bioorg Med Chem Lett, 23 (23): 6377-89. [PMID:24125884]