S1P 1 -selective agonist prodrug IMMH002 is phosphorylated in rats to form an S-configured enantiomer: Synthesis, verification, and biological activity of the in vivo active metabolite.
Bioorganic & Medicinal Chemistry Letters(2020)
Abstract
IMMH002 (1), a prodrug for a sphingosine-1-phosphate receptor 1 (S1P1) agonist, is converted to the monophosphate ester, which has an immunomodulatory effect. Starting from prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after the chiral resolution of the key intermediate by chiral high-performance liquid chromatography and the absolute configuration was determined by circular dichroism. In the in vitro homogeneous time-resolved fluorescence-IP1 functional assay, the (S)-enantiomer showed much higher S1P1 activity and selectivity than the (R)-enantiomer. In the pharmacokinetic study, the ex vivo o-phthaldialdehyde derivatization protocol showed that the phosphate of 1 in rats was the S-configured enantiomer with >99% enantiomeric excess.
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Key words
S1P1,Immunomodulatory effect,Monophosphate ester,Absolute configuration,OPA derivatization protocol
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