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SAR studies of 3-arylpropionic acids as potent and selective agonists of sphingosine-1-phosphate receptor-1 (S1P 1) with enhanced pharmacokinetic properties

Yan, Lin ; Huo, Pei ; Hale, Jeffrey J. ; Mills, Sander G. ; Hajdu, Richard ; Keohane, Carol A. ; Rosenbach, Mark J. ; Milligan, James A. ; Shei, Gan-Ju ; Chrebet, Gary ; Bergstrom, James ; Card, Deborah ; Mandala, Suzanne M.

Bioorganic & Medicinal Chemistry Letters, 2007, Vol.17(3), pp.828-831 [Peer Reviewed Journal]

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  • Title:
    SAR studies of 3-arylpropionic acids as potent and selective agonists of sphingosine-1-phosphate receptor-1 (S1P 1) with enhanced pharmacokinetic properties
  • Author: Yan, Lin ; Huo, Pei ; Hale, Jeffrey J. ; Mills, Sander G. ; Hajdu, Richard ; Keohane, Carol A. ; Rosenbach, Mark J. ; Milligan, James A. ; Shei, Gan-Ju ; Chrebet, Gary ; Bergstrom, James ; Card, Deborah ; Mandala, Suzanne M.
  • Description: Structure–activity relationship (SAR) studies of 3-arylpropionic acids—a class of novel S1P 1 selective agonists—by introducing substitution to the propionic acid chain and replacing the adjacent phenyl ring with pyridine (indicated by alphabetic letters in the Figure) led to a series of modified 3-arylpropionic acids with enhanced half-life in rat. These analogs exhibited longer half-life in rat than did unmodified 3-arylpropionic acids, suggesting that metabolic oxidation on the propionic acid chain, particularly at the C3 benzylic position of 3-arylpropionic acids, is probably responsible for their short half-life in rodent. Structure–activity relationship (SAR) studies of 3-arylpropionic acids—a class of novel S1P 1 selective agonists—by introducing substitution to the propionic acid chain and replacing the adjacent phenyl ring with pyridine led to a series of modified 3-arylpropionic acids with enhanced half-life in rat. These analogs (e.g., cyclopropanecarboxylic acids) exhibited longer half-life in rat than did unmodified 3-arylpropionic acids. This result suggests that metabolic oxidation at the propionic acid chain, particularly at the C3 benzylic position of 3-arylpropionic acids, is probably responsible for their short half-life in rodent.
  • Is Part Of: Bioorganic & Medicinal Chemistry Letters, 2007, Vol.17(3), pp.828-831
  • Identifier: ISSN: 0960-894X ; DOI: 10.1016/j.bmcl.2006.10.057
  • Subjects: Sphingosine-1-Phosphate (S1p) Receptors ; Agonists ; Lymphocyte Lowering ; Immunosuppression ; Transplantation ; Multiple Sclerosis ; 3-Arylpropionic Acids
  • Language: English

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