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

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 (<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