Insights into the metabolic characteristics of aminopropanediol analogues of SYLs as S1P1 modulators: from structure to metabolism

SYL927 and SYL930, two aminopropanediol analogues, are novel Sphingosine-1-phosphate receptor 1 (S1P1) modulators with higher selectivity and pharmacological activity compared with FTY720. Although the immunosuppressive activity of SYLs has been well demonstrated, information regarding the metabolic fates of the two chemicals is limited except for the CYP-catalyzed hydroxylation of SYL930. In this study, the biotransformation schemes of the two promising chemicals were investigated and compared using liver microsomes, S9 fractions and recombinant enzymes, and relevant molecular mechanism was primarily demonstrated by ligand-enzyme docking analysis (CDOCKER). As a result, the hydroxylation at alkyl chain on oxazole ring by the action of CYPs was found for both SYLs in vivo. The SULT-catalyzed sulfonation of the hydroxide was observed for SYL927 while the ADH/ALDH-catalyzed oxidation was only discovered for SYL930. The docking analysis suggested that specific non-covalent forces and/or bonding conformations of the hydroxides with biomacromolecules might be involved in the disparate metabolism of SYLs. Exploring the metabolic characteristics will help clarify the substance base for efficacy and safety of the two drugs. The uncovered structure-metabolism relationship in this study may provide an implication for the design and optimization for other S1P modulators.