fty-720p and Multiple-Sclerosis

Fingolimod (Gilenya; FTY720), a synthetic compound based on the fungal secondary metabolite myriocin (ISP-I), is a potent immunosuppressant that was approved (September 2010) by the U.S. FDA as a new treatment for multiple sclerosis (MS). Fingolimod was synthesized by the research group of Tetsuro Fujita at Kyoto University in 1992 while investigating structure-activity relationships of derivatives of the fungal metabolite ISP-I, isolated from Isaria sinclairii. Fingolimod becomes active in vivo following phosphorylation by sphingosine kinase 2 to form fingolimod-phosphate, which binds to extracellular G protein-coupled receptors, sphingosine 1-phosphates, and prevents the release of lymphocytes from lymphoid tissue. Fingolimod is orally active, which is unique among current first-line MS therapies, and it has the potential to be used in the treatment of organ transplants and cancer. This review highlights the discovery and development of fingolimod, from an isolated lead natural product, through synthetic analogues, to an approved drug.

Topics: Fatty Acids, Monounsaturated; Fingolimod Hydrochloride; Hypocreales; Immunosuppressive Agents; Multiple Sclerosis; Propylene Glycols; Sphingosine; Structure-Activity Relationship; United States; United States Food and Drug Administration

The sphingosine-1-phosphate-1 (S1P

Topics: Animals; beta-Arrestins; Dogs; Drug Design; Encephalomyelitis, Autoimmune, Experimental; Heart Rate; Humans; Isoxazoles; Lymphocyte Count; Lymphocytes; Male; Mice; Multiple Sclerosis; Rats; Sphingosine-1-Phosphate Receptors; Structure-Activity Relationship; Triazoles

We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.070 μM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 μM; 5: EC(50)=1.5 μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.

Topics: Animals; Area Under Curve; Cardiovascular Diseases; Chemistry, Physical; Drug Design; Female; Humans; Immunosuppressive Agents; In Vitro Techniques; Kinetics; Lymphocytes; Models, Chemical; Multiple Sclerosis; Quinolones; Rats; Rats, Inbred Lew; Receptors, Lysosphingolipid; Structure-Activity Relationship

Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (-)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability.

Topics: Administration, Oral; Animals; Crystallography, X-Ray; Immunosuppressive Agents; Lymphopenia; Mice; Models, Molecular; Multiple Sclerosis; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Prodrugs; Receptors, Lysosphingolipid; Structure-Activity Relationship; Tetrahydronaphthalenes