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

  • ACS Med Chem Lett. 2013 Jan 4;4(3):333-7. doi: 10.1021/ml300396r.
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
  • 1. Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
  • 2. Novartis Institute for Biomedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
PMID: 24900670 DOI: 10.1021/ml300396r
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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