Synthesis and biological evaluation of conformationally constrained sphingosine-1-phosphate analogs as subtype selective S1P receptor agonist/antagonist

FTY720 (Fingolimod™) represents a new generation of immunosuppressant that modulates lymphocyte trafficking by interacting with the SIP! receptor. It also provides a template molecule for studying the molecular biology of SIP receptors and related enzymes (kinases and phosphatases). In this study, a two dimensional library of conformationally constrained analogs of FTY720 was synthesized and evaluated both in vitro and in vivo. A series of new compounds with diverse biological activities were discovered. One of these compounds, VPC01091, was phosphorylated exclusively in vivo. VPC01091 induced lymphopenia while avoiding some of the adverse effects of FTY720. Four stereoisomers of VPC01091 were asymmetrically synthesized in high optical purity. In vitro assessment documented that two of the four isomers were SphK2 substrates, their phosphorylated species are potent SIP! receptor agonists and three of the isomers are potent SIP3 antagonists. After oral administration in mice, two compounds evoked lymphopenia, but their duration of action differed markedly. The discovery and synthesis of VPC01091 isomers revealed a low toxicity analog of FTY720 and, in addition the most potent S1P3 antagonist reported to date.

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Digitization of this thesis was made possible by a generous grant from the Jefferson Trust, 2015.

Thesis originally deposited on 2016-04-29 in version 1.28 of Libra. This thesis was migrated to Libra2 on 2017-03-23 16:36:55.