S1P1-selective agonist prodrug IMMH002 is phosphorylated in rats to form an S-configured enantiomer: Synthesis, verification, and biological activity of the in vivo active metabolite.,Bioorganic & Medicinal Chemistry Letters

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S1P1-selective agonist prodrug IMMH002 is phosphorylated in rats to form an S-configured enantiomer: Synthesis, verification, and biological activity of the in vivo active metabolite.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-03-26 , DOI: 10.1016/j.bmcl.2020.127141
Qiong Xiao ₁ , Minwan Hu ₂ , Si Chen ₁ , Jing Jin ₃ , Li Li ₁ , Jinping Hu ₂ , Ping Xie ₂ , Dali Yin ₁

Affiliation

IMMH002 (1), a prodrug for a sphingosine-1-phosphate receptor 1 (S1P1) agonist, is converted to the monophosphate ester, which has an immunomodulatory effect. Starting from prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after the chiral resolution of the key intermediate by chiral high-performance liquid chromatography and the absolute configuration was determined by circular dichroism. In the in vitro homogeneous time-resolved fluorescence-IP1 functional assay, the (S)-enantiomer showed much higher S1P1 activity and selectivity than the (R)-enantiomer. In the pharmacokinetic study, the ex vivo o-phthaldialdehyde derivatization protocol showed that the phosphate of 1 in rats was the S-configured enantiomer with >99% enantiomeric excess.

中文翻译：

S1P1选择性激动剂前药IMMH002在大鼠中被磷酸化，形成S-配置的对映异构体：体内活性代谢产物的合成，验证和生物活性。

IMMH002（1）是一种鞘氨醇1-磷酸受体1（S1P1）激动剂的前药，被转化为具有免疫调节作用的单磷酸酯。从前手性氨基醇1开始，合成了外消旋和对映体纯的1的磷酸盐。通过手性高效液相色谱对关键中间体进行手性拆分后，可获得纯对映体，并通过圆二色性确定了绝对构型。在体外均相时间分辨荧光-IP1功能测定中，（S）-对映体比（R）-对映体显示出更高的S1P1活性和选择性。在药代动力学研究中，离体邻苯二甲醛衍生化方案表明，大鼠中1的磷酸盐是S-构型对映异构体，对映体过量> 99％。

更新日期：2020-04-20

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