Asymmetric Synthesis of Conformationally Constrained Fingolimod Analogues--discovery of an Orally Active Sphingosine 1-phosphate Receptor Type-1 Agonist and Receptor Type-3 Antagonist

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2007 Nov 13

PMID 17994678

Citations 31

Authors

Ran Zhu

Ashley H Snyder

Yugesh Kharel

Lisa Schaffter

Qin Sun

Perry C Kennedy

Kevin R Lynch

Timothy L Macdonald

Affiliations

Soon will be listed here.

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.

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