A potent and selective S1P(1) antagonist with efficacy in experimental autoimmune encephalomyelitis

  • Chem Biol. 2012 Sep 21;19(9):1142-51. doi: 10.1016/j.chembiol.2012.07.016.
Jean Quancard  1 ,  Birgit Bollbuck ,  Philipp Janser ,  Daniela Angst ,  Frédéric Berst ,  Peter Buehlmayer ,  Markus Streiff ,  Christian Beerli ,  Volker Brinkmann ,  Danilo Guerini ,  Paul A Smith ,  Timothy J Seabrook ,  Martin Traebert ,  Klaus Seuwen ,  René Hersperger ,  Christian Bruns ,  Frédéric Bassilana ,  Marc Bigaud
Affiliations
  • 1. Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. [email protected]
PMID: 22999882 DOI: 10.1016/j.chembiol.2012.07.016
Abstract

Lymphocyte trafficking is critically regulated by the Sphingosine 1-phosphate receptor-1 (S1P(1)), a G protein-coupled receptor that has been highlighted as a promising therapeutic target in autoimmunity. Fingolimod (FTY720, Gilenya) is a S1P(1) receptor agonist that has recently been approved for the treatment of multiple sclerosis (MS). Here, we report the discovery of NIBR-0213, a potent and selective S1P(1) antagonist that induces long-lasting reduction of peripheral blood lymphocyte counts after oral dosing. NIBR-0213 showed comparable therapeutic efficacy to fingolimod in experimental autoimmune encephalomyelitis (EAE), a model of human MS. These data provide convincing evidence that S1P(1) antagonists are effective in EAE. In addition, the profile of NIBR-0213 makes it an attractive candidate to further study the consequences of S1P(1) receptor antagonism and to differentiate the effects from those of S1P(1) agonists.

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