title: 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.affiliation: Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. jean.quancard@novartis.com
authors.forename: Jean
authors.initials: J
authors.lastname: Quancard
authors.forename: Birgit
authors.initials: B
authors.lastname: Bollbuck
authors.forename: Philipp
authors.initials: P
authors.lastname: Janser
authors.forename: Daniela
authors.initials: D
authors.lastname: Angst
authors.forename: Frédéric
authors.initials: F
authors.lastname: Berst
authors.forename: Peter
authors.initials: P
authors.lastname: Buehlmayer
authors.forename: Markus
authors.initials: M
authors.lastname: Streiff
authors.forename: Christian
authors.initials: C
authors.lastname: Beerli
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: Danilo
authors.initials: D
authors.lastname: Guerini
authors.forename: Paul A
authors.initials: PA
authors.lastname: Smith
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Seabrook
authors.forename: Martin
authors.initials: M
authors.lastname: Traebert
authors.forename: Klaus
authors.initials: K
authors.lastname: Seuwen
authors.forename: René
authors.initials: R
authors.lastname: Hersperger
authors.forename: Christian
authors.initials: C
authors.lastname: Bruns
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bassilana
authors.forename: Marc
authors.initials: M
authors.lastname: Bigaud
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004151:Dipeptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*; D000081025:Sphingosine-1-Phosphate Receptors; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000814:Aniline Compounds; D004151:Dipeptides; C000589382:NIBR-0213; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors