Novel Immunomodulator FTY720 Is Phosphorylated in Rats and Humans To Form a Single Stereoisomer. Identification, Chemical Proof, and Biological Characterization of the Biologically Active Species and Its Enantiomer

Abstract

In vivo phosphorylation of FTY720 (1) in rats and humans resulted exclusively in the biologically active (S)-configured enantiomer, which was proven by an ex vivo o-phthaldialdehyde derivatization protocol especially elaborated for phosphates of 1. Starting from the prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after purification of a partially protected key intermediate on an enantioselective support. The absolute stereochemistry was determined by X-ray diffraction.

Absorption and Disposition of the Sphingosine 1-Phosphate Receptor Modulator Fingolimod (FTY720) in Healthy Volunteers: A Case of Xenobiotic Biotransformation Following Endogenous Metabolic Pathways

“…In contrast to fingolimod, its phosphate has an asymmetric center and can, therefore, exist as one of two enantiomers or a mixture of the two. As described previously (Albert et al, 2005), only the (S)-enantiomer was detected in human blood, both at early (12 h) and later times after dosing (72 h). The (R)-enantiomer was not detected (limit of detection: 3% of total fingolimod phosphate).…”

“…The compound is metabolically phosphorylated to form (S)-configured fingolimod phosphate. The latter is a potent agonist at different sphingosine 1-phosphate receptors, including those of type 1, whereas the (R)-enantiomer, which was not observed as a metabolite, and fingolimod itself show low or negligible activity at these receptors (Hale et al, 2004;Albert et al, 2005). Activation of type 1 sphingosine 1-phosphate receptors on lymphocytes by (S)-fingolimod phosphate results in suppression of the egress of lymphocytes from lymph nodes and prevention of their recirculation to other organs, including the central nervous system (Chiba, 2005;Brinkmann, 2007).…”

Asymmetric Synthesis of Conformationally Constrained Fingolimod Analogues—Discovery of an Orally Active Sphingosine 1-Phosphate Receptor Type-1 Agonist and Receptor Type-3 Antagonist

“…6 In vivo phosphorylation of 1 by Sphk2 a produces the S-phosphate species 1-P specifically, 7 which mimics much of S1P's (2-P in Chart 1 is an important extracellular lipid mediator) biological behavior. Compound 2-P signals cells via five GPCRs: S1P [1][2][3][4][5] (formerly, EDG1, EDG5, EDG3, EDG6, and EDG8).…”

FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration

“…27 FTY720p was synthesized in racemic form from FTY720 using a modified version of a previously described method. 28 D-erythro-sphingosine-1-phosphate (S1P) was purchased from Biomol International, LP (Plymouth Meeting, PA, USA) and dissolved in DMSO. Pertussis toxin (PTX) was purchased from Sigma-Aldrich (P2980, St Louis, MO, USA).…”