Characterization of a Sphingosine‐1‐phosphate Receptor Antagonist

Abstract

Sphingosine 1‐phosphate (S1P) is an extracellular lipid mediator that acts via a set of G‐protein‐coupled receptors (S1P1 – S1P5) to influence angiogenesis, immune cell trafficking, cell migration, proliferation and survival. The S1P receptor agonist prodrug, FTY720, is an immunomodulator that is in late stage clinical trials for multiple sclerosis. In the course of making conformationally‐constrained FTY720 analogs, we discovered multiple S1P receptor type‐selective compounds including antagonists such as VPC03090‐P. This compound is a pro‐drug that is converted to the active compound, VPC03090‐P, by sphingosine kinase 2. The parent compound is orally available and long lived; the ratio of active to parent drug in mouse plasma at 24 hours post dosing is 20:1. VPC03090‐P behaves as a competitive antagonist at the S1P1, S1P3 and S1P5 receptors, shifting agonist concentration‐response curves in both GTP[γ‐35S] binding and calcium mobilization assays by one log order or more when present at a concentration of 1 μM. Studies of the effect of this compound on lymphocyte trafficking and capillary permeability are ongoing. We anticipate that this unique tool will help elucidate the complex nature of S1P signaling. This research is supported by NIH grants R01 GM067958 and T32 GM007055.