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. 2013 Jan 4;4(3):333-7.
doi: 10.1021/ml300396r. eCollection 2013 Mar 14.

Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator

Shifeng Pan  1 , Nathanael S Gray  1 , Wenqi Gao  1 , Yuan Mi  1 , Yi Fan  1 , Xing Wang  1 , Tove Tuntland  1 , Jianwei Che  1 , Sophie Lefebvre  1 , Yu Chen  1 , Alan Chu  1 , Klaus Hinterding  2 , Anne Gardin  2 , Peter End  2 , Peter Heining  2 , Christian Bruns  2 , Nigel G Cooke  2 , Barbara Nuesslein-Hildesheim  2
Affiliations

Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator

Shifeng Pan et al. ACS Med Chem Lett. .

Abstract

A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing-remitting multiple sclerosis.

Keywords: S1P receptor; S1P1 agonist; lymphocytes.

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Figures

Figure 1
Figure 1
Structures of FTY720, FTY720-phosphate, and their analogues.
Figure 2
Figure 2
Amino carboxylate to mimic amino phosphate.
Figure 3
Figure 3
Binding mode of compound 2 in S1P1. The electrostatic surface is color coded: blue is positively charged, red is negatively charged, and green is hydrophobic.
Figure 4
Figure 4
PK/PD relationship of compound 32 after oral administration of 1 mg/kg to Lewis rats (n = 3).
See this image and copyright information in PMC

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