设计和合成鞘氨醇-1-磷酸受体 1 激动剂 IMMH001 的类似物，提高人血中的磷酸化速率。
Design and synthesis of analogues of the sphingosine-1-phosphate receptor 1 agonist IMMH001 with improved phosphorylation rate in human blood.
机构信息
Department of Medicinal Chemistry, State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
Departments of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
出版信息
Bioorg Med Chem. 2020 Nov 1;28(21):115722. doi: 10.1016/j.bmc.2020.115722. Epub 2020 Aug 26.
IMMH001, which is a prodrug for sphingosine-1-phosphate receptor 1 (S1P) 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 是一种鞘氨醇-1-磷酸受体 1（S1P）激动剂的前药，在体内可被鞘氨醇激酶 1（SphK1）和鞘氨醇激酶 2（SphK2）转化为其单磷酸酯（S）-IMMH001-P 的活性形式。在这项研究中，我们基于结构信息设计了 IMMH001 的头基修饰类似物，并采用高效模块化合成策略进行了制备。这些类似物在人血液中的磷酸化率高于母体化合物。这些结果表明，IMMH001 头基部分的反式羟甲基基团可防止前手性羟甲基被激酶和 ATP 磷酸化。这些类似物可能具有更好的治疗潜力。
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