Orally active, highly S1P1 subtype-selective sphingosine-1-phosphate (S1P) receptor antagonist with in vitro and in vivo efficacy.
TASP0277308 is an orally active, highly S1P1 subtype-selective sphingosine-1-phosphate (S1P) receptor antagonist (IC50 = 2.7/4.2 nM against 0.1 nM S1P for binding mouse/human S1P1; IC50 >8.7 μM for S1P2-5). TASP0277308 effectively inhibits S1P1-mediated GTPγS membrane binding, cAMP response and chemotaxis (IC50 = 7.8, 3.5, 15 nM, respectively, agianst 10 nM S1P; hS1P1-expressing HEK293 or CHO) and demonstrates in vivo efficacy in various animal disease models, including collagen-induced arthritis and tumor angiogenesis in mice (10-100 mg/kg bid po), as well as neuropathic pain in rats (0.6-3 mg/kg via acute po or ip, acute 30 nmol or daily 10 nmol intrathecal injection).
Sphingosine 1-Phosphate Receptor Subtype 1 as a Therapeutic Target for Brain Trauma
Journal of Neurotrauma, 35(13), 1452-1466 (2018)
S1P1 Modulator-Induced G ?i Signaling and ?-Arrestin Recruitment Are Both Necessary to Induce Rapid and Efficient Reduction of Blood Lymphocyte Count In Vivo
Molecular Pharmacology, 93(2), 109-118 (2018)
Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain
Proceedings of the National Academy of Sciences of the USA, 116(21), 10557-10562 (2019)
Amelioration of collagen-induced arthritis by a novel S1P1 antagonist with immunomodulatory activities
Journal of immunology (Baltimore, Md. : 1950), 188(1), 206-215 (2012)
Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation
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