Design and synthesis of selective sphingosine-1-phosphate receptor 1 agonists with increased phosphorylation rates.

ABSTRACT: FTY720 and IMMH002, prodrugs for sphingosine-1-phosphate receptor 1 (S1P₁) agonists, show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats. In this study, FTY720 or IMMH002 analogues (21-24) were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms. Target compounds were synthesized via a convergent route using the key and optically pure building block 9, which was first synthesized via asymmetrically catalyzed amination. The phosphorylation rates of these analogues in rat or human blood were compared. The new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the

SUBMITTER: Xiao Q 

PROVIDER: S-EPMC7332640 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature