NIBR-0213

Research use only, not for human use.

NIBR-0213, a potent and selective S1P(1) antagonist, has efficacy in experimental autoimmune encephalomyelitis.

NIBR-0213, a potent and selective S1P(1) antagonist, has efficacy in experimental autoimmune encephalomyelitis.(In Vitro):In Ca2+ mobilization assays, NIBR-0213 displayed an inhibitory activity on hS1P1 with an IC50 of 2.5 nM whereas it was inactive (IC50 > 10 μM) on S1P2, S1P3, and S1P4. In GTPγ35S assays, NIBR-0213 displayed potent and comparable potency on human and rat S1P1 (IC50 of 2.0 nM and 2.3 nM, respectively), whereas on mouse S1P1 a slightly reduced IC50 of 8.5 nM was measured. NIBR-0213 showed an ～3,000-fold selectivity against human S1P5 in the GTPγ35S assay (Figure 3A). On S1P4, a weak agonistic activity was detected with an EC50 of 245 nM. Schild plot analysis indicated that NIBR-0213 is a competitive S1P1 antagonist with a calculated Kd of 0.37 ± 0.031 nM.(In Vivo):NIBR-0213 increased in a dose-dependent manner the leakage of plasma proteins into lung parenchyma, as measured by the increase in EBD in lung tissues at 6 hr posttreatment (time of Emax on PBL). A maximum of 4–5-fold EBD increase versus vehicle controls was observed with 0.3 mg/kg. An ED50 of ～0.1 mg/kg could be estimated, i.e., in the range of the ED50 for the effects on PBL counts. NIBR-0213 given orally at 30 mg/kg to rats reduced the PBL counts by 75%–85% within 14 hr and maintained this effect up to 24 hr posttreatment.

NIBR-0213 displays an inhibitory activity on hS1P1?with an IC50?of 2.5?nM whereas it is inactive (IC50?>10?μM) on S1P2, S1P3, and S1P4?in Ca2+?mobilization assays.NIBR-0213 displays potent and comparable potency on human and rat S1P1?(IC50?of 2.0?nM and 2.3?nM, respectively) in GTPγ35S assays, whereas on mouse S1P1?with an IC50?of 8.5?nM.NIBR-0213 shows an ～3,000-fold selectivity against human S1P5?in the GTPγ35S assay. NIBR-0213 is a competitive S1P1?antagonist with a calculated Kd?of 0.37±0.031?nM.

NIBR-0213 (given orally at 30?mg/kg to rats) reduces the peripheral blood lymphocyte?(PBL) counts by 75%-85% within 14?hr and maintained this effect up to 24?hr posttreatment.NIBR-0213 (30?mg/kg and 60?mg/kg) is efficacious when given therapeutically in a mouse experimental autoimmune encephalomyelitis (EAE) model.The PK properties of NIBR-0213 shows a moderate clearance (26?mL/min/kg) and a high oral bioavailability (69%), leading to significant exposure after oral dosing. Animal Model:Lewis or Wistar rats (220-250 g, males)Dosage:30?mg/kg Administration:Orally Result:Reduced the PBL counts by 75%-85% within 14?hr and maintained this effect up to 24?hr posttreatment.Animal Model:C57BL/6 mice bearing EAE model Dosage:30?mg/kg and 60?mg/kg Administration:30?mg/kg twice per day (BID) for 3?days and then increased to 60?mg/kg BID until the remainder of the experiment. In total, the treatment lasted 26?days Result:Resulted in a gradual reduction in disease-scores, with a divergence from vehicle controls that became significant after 5?days.

NIBR 0213 | NIBR0213

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1233332-14-3

464.99

C27H29ClN2O3

>98% (HPLC)

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C[C@H](NC(=O)c1c(C)cc(cc1C)-c1cccc(N[C@H](C)c2ccc(Cl)c(C)c2)c1)C(O)=O

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(-20℃)

With Ice Pack

≥ 2 years