Demyelination in Organotypic Slice Cultures is Attenuated by BAF312 (Siponimod)

Abstract

Copyright: © 2016 O’Sullivan C. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The therapeutic value of sphingosine-1 phosphate receptor (S1PR) modulation was highlighted by the success of fingolimod (pFTY720) in the clinical management of relapsing remitting multiple sclerosis (MS). Great effort was then made to generate high selectivity agonists towards certain S1PR subtypes. Of particular interest were agonists with selectivity towards the S1PR1 subtype with little or no activity at the S1PR3. This was in large part due to preclinical studies in mice that suggested the transitory bradycardia that occurred after the introductory dose of pFTY720 may be attributable to the S1PR3 subtype [1,2]. Furthermore, favourable properties associated with the S1PR1 and S1PR5 subtypes, such as the key role S1PR1 plays in lymphocyte migration and the reported role of S1PR5 on oligodendrocyte function and myelination, made these attractive receptor subtypes to target [3,4]. This resulted in the synthesis of BAF312 (Siponimod), a second generation S1PR modulator selective towards the S1PR1/S1PR5 subtypes [1].