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J Med Chem. 2007 Dec 13;50(25):6428-35. Epub 2007 Nov 10.

Asymmetric synthesis of conformationally constrained fingolimod analogues--discovery of an orally active sphingosine 1-phosphate receptor type-1 agonist and receptor type-3 antagonist.

Author information

1
Department of Chemistry, University of Virginia, McCormick Road, Charlottesville, Virginia 22904-4319, USA.

Abstract

Compound 1 (FTY720, Fingolimod) represents a new generation of immunosuppressant that modulates lymphocyte trafficking by interacting with the S1P(1) receptor. Compound 1 also provides a template molecule for studying the molecular biology of S1P receptors and related enzymes (kinases and phosphatases). In this study, two conformationally constrained analogues of 1 ( 3a and 3c) were asymmetrically synthesized in high optical purity. In vitro assessment documented that both analogues are Sphk2 substrates, their phosphorylated species are potent S1P(1) receptor agonists, and 3a-P is a potent S1P 3 antagonist. After oral administration in mice, both compounds evoked lymphopenia, but their duration of action differed markedly.

PMID:
17994678
PMCID:
PMC2895489
DOI:
10.1021/jm7010172
[Indexed for MEDLINE]
Free PMC Article

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