fingolimod (gilenya) presented by matthew brickey, tim robinson, tom mcginnis, and katie youmans
TRANSCRIPT
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Fingolimod (Gilenya)
Presented by Matthew Brickey, Tim Robinson, Tom McGinnis, and Katie
Youmans
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Outline
• Disease: Multiple Schlerosis• Discovery of Fingolimod-Gilenya• Synthesis and lead modification• Mechanism of action• Pharmacology • Questions
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Multiple Sclerosis
• Degenerative nerve disease• Characterized by defective immune
system response resulting in nerve damage
• Cause is unknown• Difficult diagnosis
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Multiple Sclerosis (MS)
4 types of MS• Relapsing-remitting (RR)• Primary Progressive (PP)• Secondary progressive (SP)• Progressing relapsing (PR)
• RR often progresses into SP over time
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DISCOVERY
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Initial Antifungal Agents
• Cyclosporin A-reported in 1976 (fungus origin)• FK506-isolated in 1987 (bacterium origin)• These set up a foundation for the screening of
new fungi and other microbes in the pursuit of new immunosuppressants.
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Studying Isaria sinclairii
• Tetsuro Fujita began focusing on Isaria sinclairii in the late 1980s and early 1990s.
• This fungus is native to Asia, mainly China, Korea, and Japan.
• Classified as an entomopathogenic fungus.
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Isaria sinclairii fungal development
• Spreads by infecting insect larvae with its fungal spores
• Acts as a parasite, growing in and ultimately killing the insect
• Afterwards, colonizes the insect cadaver and develops white fruiting bodies (6cm tall)
• Fruits in spring and summer
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In Vitro Assay
• To screen for immunosuppressive activity• Fujita used a mouse allogeneic mixed
lymphocyte reaction (MLR) assay• Spleen cells from two different strains of mice
were cocultured and alloantigen was added to stimulate T-cell proliferation
• Samples were evaluated for inhibition of proliferation of T-cells (reported as IC50 value)
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In Vivo Assay
• Performed by transplanting the dorsal skin of one rat (strain LEW) to the lateral thorax of the second rat (strain F344)
• Daily intraperitoneal administration until the skin grafts were rejected (90% necrosis)
• Compounds were scored on their ability to prolong rat skin graft survival.
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Importance of Assays
• Lead to the eventual development of fingolimod
• The evaluation process guided the isolation of a compound with immunosuppressant activity– They called it ISP-I (below)
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ISP-I
• Identical to previously isolated antifungal agents– Myriocin and thermozymocidine
• Pros:– Found to be 5-10 fold more potent than cyclosporin A
in the MLR assay– Also prolonged rat skin graft survival better.
• Cons: – Found to be toxic at a smaller dose than Cyclosporin A– Poorly soluble
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Improving ISP-I
• Goal:– To simplify the structure and improve the physical
characteristics (e.g. solubility) and biological function
• Between 1995 and 1998, around 50 different analogues were reported, with published results from both in vitro and in vivo assays
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ISP-I-28
• First analogue of interest• Less toxic, prolonged survival, but less potent
in MLR assay• Reduced carboxylic acid and 14-ketone to
alcohols
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• Removed three hydroxy groups, ISP-I-36• Improved activity and survival
• Shortened chain to 14 carbons to create ISP-I-55• More potent immunosuppressant in both in vivo and
in vitro, double survival time in skin graft assay
Next Steps
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Final Modification
• Introduced an aromatic moiety-believed to improve activity by restricting conformation
• Placement could increase or decrease activity of drug-one position off 10-fold less potent
• Led to fingolimod, with improved activity, less toxicity, and better solubility
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Synthesis
• 13 methods for Fingolimod, Fingolimod-P• First in 1995• Yields remained at or below 25 % until 2005• Convenient method an improvement on 1995
synthesis, a three step reaction of precursor to Fingolimod (2008)
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Petasis Reaction (Sugiyama, 2005)
• Five step synthesis• Couples boronic acids, amines, carbonyls• Form amino alcohols• Overall Yield of 28%
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Kim 2006• Start with tris-(hydroxymethyl)aminomethane
(TRIS)• Convert to aldehyde, then alkyne• Couple to aryl iodide via Sonogashira reaction• Hydrogenate, treat with acid, purify• Cheap, practical, 64% overall yield Fingolimod
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Mechanism of Action
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G Protein Coupled Receptors
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The Nuts and Bolts of it
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Pharmacology
• Marketed as Gilenya• First orally active treatment• Tested on patients with RR-MS–60% decreased in relapse rate
• When compared to Injection treatments growth of new lesions and plaques was significantly reduced
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Questions?