Discovery of Potent 3,5-Diphenyl-1,2,4-oxadiazole Sphingosine-1-phosphate-1 (S1P sub(1)) Receptor Agonists with Exceptional Selectivity against S1P sub(2) and S1P sub(3)

Discovery of Potent 3,5-Diphenyl-1,2,4-oxadiazole Sphingosine-1-phosphate-1 (S1P sub(1)) Receptor Agonists with Exceptional Selectivity against S1P sub(2) and S1P sub(3)

A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P sub(1)) receptor agonists with minimal affinity for the S1P sub(2) and S1P3 receptor subtypes. Analogue 26 (S1P sub(1) IC sub(50) = 0.6 nM) has an excellent pharmacokinetics profile...

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Veröffentlicht in:Journal of medicinal chemistry 2005-10, Vol.48 (20), p.6169-6173
Hauptverfasser: Li, Z, Chen, W, Hale, J J, Lynch, CL, Mills, S G, Hajdu, R, Keohane, CA, Rosenbach, MJ, Milligan, JA, Shei, G-J, Chrebet, G, Parent, SA, Bergstrom, J, Card, D
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Sprache:eng
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Zusammenfassung:A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P sub(1)) receptor agonists with minimal affinity for the S1P sub(2) and S1P3 receptor subtypes. Analogue 26 (S1P sub(1) IC sub(50) = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P sub(3) receptor agonism is not a component of immunosuppressive efficacy.
ISSN:0022-2623
DOI:10.1021/jm0503244