Abstract
A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P(1) agonists. The extensive structure-activity relationship studies for these analogues were reported. Among them, 17g was identified to show high in vitro potency with reasonable free unbound fraction in plasma (F(u) > 0.5%), good brain penetration (BBR > 0.5), and desirable pharmacokinetic properties in mouse and rat. Oral administration of 1 mg/kg 17g resulted in significant peripheral lymphocytes reduction at 4 h after dose and rapid lymphocytes recovery at 24 h. 17g showed a transient lymphopenia profile in the repeated dose study in mouse. In addition, 17g also demonstrated efficacy comparable to that of FTY720 (1) in the mouse EAE model of MS.
MeSH terms
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Administration, Oral
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Animals
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism
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Brain / drug effects
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Brain / metabolism
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Disease Models, Animal
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Humans
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Immunosuppressive Agents / chemical synthesis*
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / pharmacokinetics
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Immunosuppressive Agents / pharmacology*
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Lymphocyte Count
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Lymphocytes / drug effects
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Lymphocytes / metabolism
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Magnetic Resonance Spectroscopy
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Male
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Mice
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Mice, Inbred C57BL
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Multiple Sclerosis, Relapsing-Remitting / drug therapy*
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Multiple Sclerosis, Relapsing-Remitting / metabolism
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Rats
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Receptors, Lysosphingolipid / agonists*
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Receptors, Lysosphingolipid / metabolism
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Specific Pathogen-Free Organisms
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Spectrometry, Mass, Electrospray Ionization
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Structure-Activity Relationship
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Thiadiazoles / chemical synthesis*
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Thiadiazoles / chemistry
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Thiadiazoles / pharmacokinetics
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Thiadiazoles / pharmacology*
Substances
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Immunosuppressive Agents
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Receptors, Lysosphingolipid
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Thiadiazoles