生物活性

• 描述BAF312, also called Siponimod, is a selective, potent and brain-penetrant S1P receptor modulator used to treat multiple sclerosis, with EC50 values of 0.4nM and 5nM for S1P1 and S1P3 in GTPγS binding assay, respectively. Oral administration of 1mg/kg BAF312 markedly reduced peripheral lymphocyte count, a pharmacodynamic biomarker in autoimmune diseases for S1P1 activation, by 88% in Lewis rats at 8h post treatment, with a shorter duration of action than FTY720^[1]. BAF312 also showed effect on S1P5 with EC50 of 0.98nM. Treatment with BAF312 at concentration of 1μM for 1h promote internalization of S1P1 receptors in CHO cells expressed myc-tagged human S1P1 receptors. Daily oral administration of BAF312 at dose of 0.3 or 3mg/kg for 24 days dose-dependently suppressed ongoing disease symptoms in rat EAE. BAF312 concentration-dependently activated the GIRK channel via S1P1 in atrial myocytes with EC50 value of 15.8nM^[2].
• 作用机制BAF312 is structurally based on FTY720.^[1]

• 动物研究
  剂量	Rat: 0.03 mg/kg - 3 mg/kg[2] (p.o.); 0.5 mg/kg - 5 mg/kg[3] (i.v.); 0.3 mg/kg - 30 mg/kg[3] (p.o.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Mice[4] Rats[4] Monkeys[4] Dose 8 mg/kg 3 mg/kg 1 mg/kg Administration p.o. p.o. p.o. F 0.487 0.71 T1/2 27.2 h Tmax 8 h 6.67 h 2.5 h AUClast 64060 ng·h/ml 4050 ng·h/ml 7550 ng·h/ml Cmax 2300 ng/ml 259 ng/ml 354 ng/ml

• 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
  NCT02330965	-	-	Completed	-	United States, California ... more >> Jordan Research & Education Institute: Sutter Alta Bates Summit Berkeley, California, United States, 94705 University of Southern California Los Angeles, California, United States, 90033 University of California, Davis Sacramento, California, United States, 95817 United States, Colorado University of Colorado Aurora, Colorado, United States, 80045 United States, Michigan University of Michigan Health System -Multiple Sclerosis Center Ann Arbor, Michigan, United States, 48109 Henry Ford Health System Detroit, Michigan, United States, 48202 United States, Minnesota Minneapolis Clinic of Neurology Golden Valley, Minnesota, United States, 55422 United States, New Mexico University of New Mexico: Health Sciences Center Albuquerque, New Mexico, United States, 87131 United States, New York South Shore Neurologic Associates - Multiple Sclerosis Care Center Patchogue, New York, United States, 11772 United States, North Carolina Carolinas Medical Center (CMC) Charlotte, North Carolina, United States, 28207 United States, Ohio Cleveland Clinic: Mellen Center for Multiple Sclerosis Cleveland, Ohio, United States, 44195 United States, Oregon Providence Multiple Sclerosis Center Portland, Oregon, United States, 97225 United States, Washington Swedish Neuroscience Institute Seattle, Washington, United States, 98122 Collapse <<
  NCT01185821	Relapsing Remitting Multiple S... more >>clerosis Collapse <<	Phase 2	Completed	-	-
  NCT03338998	Hemorrhagic Stroke ... more >> Intracerebral Hemorrhage (ICH) Collapse <<	Phase 2	Recruiting	March 17, 2020	United States, Connecticut ... more >> Novartis Investigative Site Recruiting New Haven, Connecticut, United States, 06520 United States, North Carolina Novartis Investigative Site Recruiting Durham, North Carolina, United States, 27710 United States, Oregon Novartis Investigative Site Recruiting Portland, Oregon, United States, 97239 Collapse <<

• 更多
• 参考文献

• [1] Pan S, Gray NS, et al. Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator. ACS Med Chem Lett. 2013 Jan 4;4(3):333-7.

  [2] Gergely P, Nuesslein-Hildesheim B, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol. 2012 Nov;167(5):1035-47.

  [3] Fryer RM, Muthukumarana A, et al. The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P₁) and hypertension (S1P₃) in rat. PLoS One. 2012;7(12):e52985.

  [4] Siponimod