Discovery of BAF312 (Siponimod),
a Potent and Selective S1P Receptor Modulator
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Abstract
A novel series of alkoxyimino derivatives as S1P<sub>1</sub> agonists were discovered through de novo design using FTY720
as the chemical starting point. Extensive structure–activity
relationship studies led to the discovery of (<i>E</i>)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic
acid (<b>32</b>, BAF312, Siponimod), which has recently completed
phase 2 clinical trials in patients with relapsing–remitting
multiple sclerosis