FTY720 S‐ene‐phosphonate is a novel pan‐antagonist of the S1P receptors that inhibits lymphocyte egress

Abstract

FTY720 phosphate, an analogue of sphingosine‐1‐phosphate (S1P) is in a phase‐III clinical study for the treatment of multiple sclerosis. FTY720P causes S1P1 receptor internalization rendering the lymphocytes unresponsive to S1P. Here we describe the first enantioselective synthesis of chiral isosteric phosphonate analogues of FTY720 and the pharmacological characterization of two enantiomers, FTY720 S‐ene phosphonate and FTY720 R‐ene phosphonate. Pharmacological analysis of the enantiomers revealed that R‐ene was a full agonist of S1P1 (EC50 38±5 nM). In contrast, S‐ene was a full antagonist of S1P1,3,4 (Ki 208 nM, 15 nM, and 1190 nM, respectively) and a partial antagonist of S1P2 and S1P4. Both enantiomers dose‐dependently inhibited lysophospholipase D (IC50 182 nM for S‐ene and 169 nM for R‐ene). When injected into mice, S‐ene caused transient peripheral lymphopenia, which is consistent with its antagonist activity at S1P1. FTY720 S‐ene phosphonate also activated ERK1/2 in a pertussis toxin‐sensitive mechanism, suggesting that it also activated a yet unidentified GPCR. FTY720 S‐ene phosphonate exerted an antiapoptotic effect in IEC‐6 intestinal epithelial cells challenged with camptothecin. S‐ene is the first pan‐antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. Supported by NIH Grants HL083187, AI80405 and CA92160.