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.
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.
Albert
Rainer
R
Novartis Institutes for BioMedical Research, Lichtstrasse 35, WSJ-507.3.02, CH-4056 Basel, Switzerland. rainer.albert@novartis.com
Hinterding
Klaus
K
Brinkmann
Volker
V
Guerini
Danilo
D
Müller-Hartwieg
Constanze
C
Knecht
Helmut
H
Simeon
Corinne
C
Streiff
Markus
M
Wagner
Trixie
T
Welzenbach
Karl
K
Zécri
Frédéric
F
Zollinger
Markus
M
Cooke
Nigel
N
Francotte
Eric
E
D000276:Adjuvants, Immunologic / Q000097:blood*; D000818:Animals; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008297:Male; D010755:Organophosphates / Q000097:blood* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D011409:Propylene Glycols / Q000097:blood*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C453461:2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butyl phosphate; D000276:Adjuvants, Immunologic; D010755:Organophosphates; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine