Gilenia

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Description

Sphingosine 1-phosphate (S1P) is an extracellular lipid mediator whose major effects are mediated through four of the S1P receptors (S1P1, S1P3, S1P4, and S1P5). S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. S1P receptors have been shown to influence cell proliferation, morphology, and migration and are also expressed on a wide range of cells that are involved in many biological processes relevant to multiple sclerosis (MS). Fingolimod (FTY720 (free base) of ) is a derivative of the fungal metabolite myriocin, a structural analog of sphingosine. In vivo, fingolimod is phosphorylated to form fingolimod-phosphate, which resembles naturally occurring S1P. Fingolimod-phosphate functions as an agonist at S1P1, S1P4, and S1P5 receptors (EC50 values of ~0.3-0.6 nM in vitro) and at 10-fold higher concentrations at S1P3 receptors (EC50 values of ~3 nM) but has no activity at S1P2 receptors. Fingolimod is a first-in-class orally bioavailable compound that has shown efficacy in advanced clinical trials for the treatment of MS through receptor-mediated actions both on the immune system and in the central nervous system. At 0.1-0.3 mg/kg it was shown to be highly effective at inhibiting the development of experimental autoimmune encephalomyelitis, an animal model of human MS, whereas concentrations 10-100-fold higher or in combination with classic immunosuppressants were required to prolong organ graft survival in animals.