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.
Click here for help
2D Structure
Click here for help
Click here for structure editor
Physico-chemical Properties
Click here for help
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
Click here for help
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+
No information available.
Summary of Clinical Use Click here for help
Siponimod was granted FDA approval in March 2019, for the treatment of relapsing forms of multiple sclerosis (secondary progressive multiple sclerosis with active disease, relapsing remitting multiple sclerosis and clinically isolated syndrome), following positive outcomes from the Phase 3 EXPAND trial NCT01665144 [5]. EMA approval followed in January 2020. Click here to link to's full list of siponimod (BAF312) trials.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Tha main aim of treatment with siponimod is to delay disability progression and preserving cognition in multiple sclerosis (MS) patients. The sphingosine 1-phosphate receptor (S1PR) pathway is a validated drug target for multiple sclerosis (MS) [10], with the S1P1,3-5-R pan-agonist fingolimod already approved as the first oral drug for the treatment of relapsing-remitting MS. S1PR agonists decrease the number of circulating peripheral blood lymphocytes [3,6] and subsequently produce an immunosuppressant effect which results in attenuation of demyelination [7] and prevents synaptic neurodegeneration in experimental MS [2] in vitro. As it has a shorter circulating half life compared to fingolimod, siponimod is expected to be less likely to cause induced lymphopenia, one of the most problematic side effects associated with fingolimod therapy.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT01665144 Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND) Phase 3 Interventional Novartis In this trial siponimod reduced the risk of disability progression in patients with SPMS. Its risk profile was similar to that of other S1P modulators. 5