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 parent compound, whereas compound 23 showed improvements in rats, but not in humans. In pharmacokinetics studies of rats, compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and IMMH002. Thus, our study not only yielded new compounds with therapeutic potential, but also showed species differences between rats and humans in response to the structural modifications, which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic.

FTY720和IMMH002，鞘氨醇-1-磷酸受体1（S1P ₁）激动剂的前药，与大鼠相比，在人体内的磷酸化水平不足和不一致。在这项研究中，FTY720或IMMH002类似物（21 - 24）设计并与经修饰头件合成以改善前体药物的生物转化到活性磷酸化形式。使用键和光学纯净的结构单元9通过收敛途径合成目标化合物，该结构单元首先通过不对称催化的胺化反应合成。比较了大鼠或人类血液中这些类似物的磷酸化率。新的甲基取代的类似物化合物21在大鼠和人类中均显示出比母体化合物更高的磷酸化率，而化合物23在大鼠中则有所改善，但在人类中却没有。在大鼠的药代动力学研究中，化合物21和23的磷酸化水平均高于FTY720和IMMH002。因此，我们的研究不仅产生了具有治疗潜力的新化合物，而且还显示了人类和人类之间对结构修饰的反应所产生的物种差异，这可能有助于预测此类临床前药的生物转化行为和功效。