Abstract
A novel series of benzoxazole-derived S1P(1) agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P(1) agonist (over S1P(3)) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Benzoxazoles / chemical synthesis*
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Benzoxazoles / pharmacology
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Binding Sites
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Calcium / metabolism
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Immunosuppressive Agents / chemical synthesis*
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Immunosuppressive Agents / pharmacology
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Lymphocyte Count
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Lymphocytes / cytology
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Lymphocytes / drug effects*
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Mice
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Models, Molecular
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Protein Binding
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Receptors, Lysosphingolipid / agonists*
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Receptors, Lysosphingolipid / metabolism
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Sensitivity and Specificity
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Sphingosine-1-Phosphate Receptors
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Structure-Activity Relationship
Substances
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Benzoxazoles
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Immunosuppressive Agents
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Receptors, Lysosphingolipid
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S1pr3 protein, mouse
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Sphingosine-1-Phosphate Receptors
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Calcium