NIBR0213 is an orally bioavailable, potent, and selective antagonist of sphingosine-1-phosphate receptor-1 (S1P1) with IC50 values of 2.5 and 2.0 nM for the hS1P1 in a Ca2+ mobilization assay and GTPγS assay, respectively. [1] It is inactive at S1P2, S1P3, and S1P4 receptors (IC50s = >20, >10, and >10 uM, respectively in a Ca2+ mobilization assay). S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation.[2] In rats, NIBR0213 (30 mg/kg) reduces peripheral blood lymphocytes by 75-85% for up to 24 hours. [1] In a mouse model of experimental autoimmune encephalitis (EAE), it significantly reduces disease severity up to 26 days, when administered at 30 mg/kg twice per day for three days, then 60 mg/kg twice per day. However, in a rat model of adjuvant-induced arthritis, chronic administration of 30 mg/kg induces pulmonary damage and chronic lung inflammation.[3]
Reference:
[1]. Quancard, J., Bollbuck, B., Janser, P., et al. A potent and selective S1P1 antagonist with efficacy in experimental autoimmune encephalomyelitis. Chem. Biol. 19(9), 1142-1151 (2012).
[2]. Huwiler, A., Kolter, T., Pfeilschifter, J., et al. Physiology and pathophysiology of sphingolipid metabolism and signaling. Biochim. Biophys. Acta. 1485(2-3), 63-99 (2000).
[3]. Bigaud, M., Dincer, Z., Bollbuck, B., et al. Pathophysiological consequences of a break in S1P1-dependent homeostasis of vascular permeability revealed by S1P1 competitive antagonism. PLoS One 11(12), e0168252 (2016).