生物活性

• 靶点	S1PR1 IC50:0.033nM

• 描述Fingolimod HCl is the hydrochloride form of Fingolimod. Fingolimod is an S1p receptor modulator and also immunosuppressant. It can be primarily phosphorylated by SPHK2 to its active form fingolimod-P. Although fingolimod-P (but not parent fingolimod) could function as an agonist at S1P1, S1P4 and S1P5 receptors with EC50 values ranging in ~0.3–0.6nM and at 10- fold higher concentrations at S1P3 receptors with EC50 values of ~3 nM^[1], it caused S1P receptors to internalize from cell membranes and induce ubiquitinylation and proteasomal degradation of the receptor. That is, effects of Fingolimod are inhibitory in the longer term on S1P receptor function^[2]. Fingolimod was used to treat for multiple sclerosis. Culture with FTY720 at concentration of 1μM for 22 hours could stimulate survival of the oligodendrocyte progenitors, and an activation of both MEK/ERK1/2 and PI3K/Akt pathways dependent on transforming to fingolimod-P by SphK could be observed^[3]. Fingolimod is highly effective in experimental autoimmune encephalomyelitis model. Administration of fingolimod at dose of 0.03 to 1 mg/kg could significant improve the symptoms of chronic experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein in mice due to the reduction of infiltration of myelin antigen-specific Th17 and Th1 cells into the central nervous system^[4].
• 作用机制The aminodiol polar head group of fingolimod could be phosphorylated by SPHK2 and the lipophilic tail is important for interacting with the hydrophobic binding pocket of the S1P receptors^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  CHO cells	-	Function assay	-	Displacement of [33P]sphingosine 1 phosphate from human S1P1 receptor expressed in CHO cells, IC50=0.84 μM.	15615513
  human BLIN-1 cells	-	Cytotoxic assay	72 h	Cytotoxicity against Ph-negative human BLIN-1 cells after 72 hrs by vital dye exclusion/flow cytometric analysis, IC50=5.5 μM.	24273632
  human BV173 cells	-	Cytotoxic assay	72 h	Cytotoxicity against Ph-positive human BV173 cells after 72 hrs by vital dye exclusion/flow cytometric analysis, IC50=6.3 μM.	24273632

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• 动物研究
  剂量	Mice: 1 mg/kg - 10 mg/kg[5] (i.p.), 0.03 mg/kg - 1 mg/kg[4] (p.o.) Rat: 3 mg/kg - 7.5 mg/kg[6] (i.v.)
  给药途径	i.p., p.o., i.v.
  动物药代数据	Animal Mice[6] Rats[6] Dogs[6] Monkeys[6] Dose 2.5 mg/kg (p.o. or i.v.) 7.5 mg/kg (p.o.) 4 mg/kg (i.v.) 3 mg/kg (p.o.) 1 mg/kg (i.v.) 3 mg/kg (p.o.) 0.1 mg/kg (i.v.) Administration p.o. i.v. p.o. i.v. p.o. i.v. F 66% (p.o.) 59% (p.o.) 60.8% (p.o.) 51% (p.o.) T1/2 25 h (p.o.) 29.3 h (p.o.) Tmax 8 h (p.o.) 8 h (p.o.) 9.3 h (p.o.) 9.3 h (p.o.) MRT 31.5 h (i.v.) 32 h (p.o.) 34.7 h (i.v.) t1/2β 24.6 h (i.v.) T1/2β 27.8 h (i.v.) Cmax 95.3 ng/ml (p.o.) 148 ng/ml (p.o.) 165 ng/ml (p.o.) 30.7 ng/ml (p.o.) CL 0.55 L/h/kg (i.v.) 9.17 ml/min/kg (i.v.) 0.666 L/h/kg (i.v.) 11.1 ml/min/kg (i.v.) 0.219 L/h/kg (i.v.) 3.65 ml/min/kg (i.v.) 0.0917 L/h/kg (i.v.) 1.528 ml/min/kg (i.v.) Vss 17.30 L/kg (i.v.) 21 L/kg (p.o.) 7.60 L/kg (i.v.) 17.3 L/kg (i.v.) AUC 3167 ng·h/ml (p.o.) 5442 ng·h/ml (i.v.) 6795 ng·h/ml (p.o.) 6027 ng·h/ml (i.v.) 8491 ng·h/ml (p.o.) 4658 ng·h/ml (i.v.) 1640 ng·h/ml (p.o.) 323 ng·h/ml (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02559765	-	-	Completed	-	United Kingdom ... more >> The University of Glasgow Glasgow, United Kingdom, G12 8LL Collapse <<
  NCT03500328	Multiple Sclerosis, Relapsing-... more >>Remitting Collapse <<	Not Applicable	Recruiting	October 31, 2022	-
  NCT03535298	Multiple Sclerosis, Relapsing-... more >>Remitting Collapse <<	Phase 4	Not yet recruiting	September 2023	United States, Ohio ... more >> Cleveland Clinic Not yet recruiting Cleveland, Ohio, United States, 44195 Contact: Tammy Skaramagas, BA    216-445-6724    skaramt1@ccf.org    Principal Investigator: Daniel Ontaneda, MD, MSc          United Kingdom University of Nottingham Not yet recruiting Nottingham, United Kingdom, NG7 2UH Contact: Sara Wilkins    +44 115 9249924 ext 66816    Sara.wilkins@nuh.nhs.uk    Principal Investigator: Nikos Evangelou, MD, DPhil Collapse <<

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• 参考文献

• [1] Brinkmann V, Davis MD, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002 Jun 14;277(24):21453-7. Epub 2002 Apr 19.

  [2] Oo ML, Thangada S, et al. Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem. 2007 Mar 23;282(12):9082-9. Epub 2007 Jan 21.

  [3] Coelho RP, Payne SG, et al. The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J Pharmacol Exp Ther. 2007 Nov;323(2):626-35. Epub 2007 Aug 28.

  [4] Chiba K, Kataoka H, et al. Fingolimod (FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-β in mouse experimental autoimmune encephalomyelitis. Int Immunopharmacol. 2011 Mar;11(3):366-72.

  [5] Blanc CA, Rosen H, et al. FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination. J Neuroinflammation. 2014 Aug 20;11:138.

  [6] FTY720

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