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

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 relationshipstudies 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.