NIBR-0213 is a potent and selective competitive S1P1 antagonist with activity against experimental autoimmune encephalomyelitis. In the GTPγ35S assay, it has IC50 values ​​of 2.0 nM and 2.3 nM for human and rat S1P1, respectively.

S1P1:8.5 nM(GTPγ35S,mouse), S1P1:2.5 nM(Ca2+ mobilization), S1P1:2.3 nM(GTPγ35S,rat), S1P1:2.0 nM(GTPγ35S,human)

In the Ca2+ assay, NIBR-0213 showed inhibitory activity against hS1P1 with an IC50 of 2.5 nM, but was inactive against S1P2, S1P3, and S1P4 (IC50 > 10 μM); in the GTPγ35S assay, NIBR-0213 showed potent and comparable potency against human and rat S1P1 (IC50 of 2.0 nM and 2.3 nM, respectively), while the IC50 for mouse S1P1 was slightly lower at 8.5 nM. [1]

METHODS: NIBR-0213 (30, 100, 300 mg/kg, oral, once daily, for two weeks) was used to treat the rat adjuvant-induced arthritis (AiA) model to explore the functional/pathophysiological consequences of the disruption of S1P1-dependent vascular permeability homeostasis caused by its competitive antagonism.
RESULTS An effective oral dose of 30 mg/kg BID was tolerated without signs of dyspnea but induced dose-dependent acute vascular lung leak and pleural effusion, which completely resolved within 3-4 days; at a supramaximal oral dose of 300 mg/kg QD, NIBR-0213 impaired lung function (increased respiratory rate and decreased tidal volume) within the first 24 hours; NIBR-0213 at doses of 30, 100, and 300 mg/kg induced moderate lung changes after two weeks, characterized by alveolar wall thickening, macrophage accumulation, fibrosis, microhemorrhage, edema, and necrosis.[2]