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

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.

• Authors: Jean Quancard, 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
• Journal: Chemistry & biology (Chem Biol) Vol. 19 Issue 9 Pg. 1142-51 (Sep 21 2012) ISSN: 1879-1301 [Electronic] United States
• PMID: 22999882 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Aniline Compounds
• Dipeptides
• NIBR-0213
• Receptors, Lysosphingolipid
• S1PR1 protein, human
• Sphingosine-1-Phosphate Receptors

Topics

• Administration, Oral
• Aniline Compounds (administration & dosage, chemistry, pharmacology, therapeutic use)
• Animals
• CHO Cells
• Cricetinae
• Cricetulus
• Dipeptides (administration & dosage, chemistry, pharmacology, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, pathology)
• Female
• Humans
• Leukocytes, Mononuclear (drug effects)
• Lymphocyte Count
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Molecular Structure
• Rats
• Rats, Inbred Lew
• Rats, Wistar
• Receptors, Lysosphingolipid (antagonists & inhibitors)
• Sphingosine-1-Phosphate Receptors
• Structure-Activity Relationship
• Substrate Specificity