Design And Synthesis Of Analogues Of The Sphingosine-1-Phosphate Receptor 1 Agonist Immh001 With Improved Phosphorylation Rate In Human Blood

IMMH001, which is a prodrug for sphingosine-1-phosphate receptor 1 (S1P(1)) agonist, is converted to the active form, its monophosphate ester (S)-IMMH001-P, by sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2) in vivo. In this study, we designed head-piece-modified analogues of IMMH001 based on structural information and prepared them with an efficient modular synthetic strategy. The analogues showed higher phosphorylation rates in human blood than the parent compound. These results indicated that the pro-R hydroxymethyl in the head-piece-moiety of IMMH001 prevents the pro-S hydroxymethyl from being phosphorylated by the kinase and ATP. The analogues may have better therapeutic potential.