TASP0277308 is a sphingosine-1-phosphate receptor 1 (S1P1) antagonist (IC50 = 4.2 nM).[1] It is selective for S1P1 over S1P3, S1P4, and S1P5 (IC50s = >10,000, >10,000, and 8,756 nM, respectively). TASP0277308 inhibits S1P-induced [35S]GTPγS binding and forskolin-induced cAMP production in HEK293 cells expressing human S1P1 (IC50s = 7.8 and 4.3 nM, respectively). It inhibits S1P-induced migration of CHO cells expressing human S1P1 (IC50 = 18 nM). In vivo, TASP0277308 (100 mg/kg) induces lymphopenia in mice. It reduces bone erosion in a mouse model of collagen-induced arthritis. Intrathecal administration of TASP0277308 (3 or 10 nmol/animal) reduces flinching and guarding behaviors in a mouse model of cancer-induced bone pain.[2]
References:
[1].Fujii, Y., Hirayama, T., Ohtake, H., et al.Amelioration of collagen-induced arthritis by a novel S1P1 antagonist with immunomodulatory activitiesJ. Immunol.188(1)206-215(2012).
[2].Grenald, S.A., Doyle, T.M., Zhang, H., et al.Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammationPain158(9)1733-1742(2017).