A Potent and Selective S1P1 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.

Inhibitors of sphingosine-1-phosphate metabolism (sphingosine kinases and sphingosine-1-phosphate lyase)

“…VPC23019 S1P 1 S1P 3 (Davis et al, 2005) VPC44116 S1P 1 (Foss Jr. et al, 2007) TASP0277308 S1P 1 NIBR0213 S1P 1 (Quancard et al, 2012) ML056 (R)-W146 S1P 1 Tarrason et al, 2011) (S)-FTY720 vinylphosphonate S1P 1 S1P 3 S1P 4 (Valentine et al, 2010) JTE013 S1P 2 (Osada et al, 2002); in combination with SK1-I, see (Chen et al, 2015) Compound 22 S1P 2 (Kusumi et al, 2015) TY52156 S1P 3 SPM242 S1P 3 ML131 S1P 4 (Oldstone et al, 2010) …”

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

“…4E). Treatment with the S1P 1 -selective functional antagonist NIBR-0213 (38) showed fivefold increase of 1-kDa Alexa Fluor 555-cadaverine accumulation in brain parenchyma at 6 h after injection, but not at 48 h after injection of NIBR-0213 (Fig. 4 F and G).…”

Structural Biology of the S1P1 Receptor

“…Finally, a series of N-biaryl(hetero) arylsulfonamide compounds originally reported in the patent literature and later optimized for pharmaceutics properties to produce NIBR-0213 (Berst et al 2007;Quancard et al 2012) have shown comparable efficacy to FTY720-P in mouse experimental autoimmune encephalomyelitus) models of human multiple sclerosis.…”