Document Report Card

ID: ALA1138321

Journal: J Med Chem

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

Authors: Zhu R, Snyder AH, Kharel Y, Schaffter L, Sun Q, Kennedy PC, Lynch KR, Macdonald TL.

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.

CiteXplore: 17994678

DOI: 10.1021/jm7010172