IMMH001, which is a prodrug for sphingosine-1-phosphate receptor 1 (S1P₁) 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.

IMMH001是鞘氨醇1-磷酸受体1（S1P ₁）激动剂的前药，通过鞘氨醇激酶1（SphK1）和鞘氨醇激酶2（SphK1）转化为活性形式，即单磷酸酯（S）-IMMH001-P。 SphK2）体内。在这项研究中，我们根据结构信息设计了IMMH001的头部修饰类似物，并采用有效的模块化合成策略对其进行了制备。该类似物在人血中显示出比母体化合物更高的磷酸化率。这些结果表明，亲- [R在的IMMH001防止亲头片基的部分羟甲基小号羟甲从由激酶和ATP磷酸化被。这些类似物可能具有更好的治疗潜力。