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

Qiong Xiao; Minwan Hu; Si Chen; Jing Jin; Li Li; Jinping Hu; Ping Xie; Dali Yin

doi:10.1016/j.bmcl.2020.127141

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

Bioorg Med Chem Lett. 2020 Jun 1;30(11):127141. doi: 10.1016/j.bmcl.2020.127141. Epub 2020 Mar 26.

Authors

Qiong Xiao¹, Minwan Hu², Si Chen¹, Jing Jin³, Li Li¹, Jinping Hu⁴, Ping Xie², Dali Yin⁵

Affiliations

¹ 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.
² Department 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.
³ Department of Pharmacology, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
⁴ Department 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. Electronic address: [email protected].
⁵ 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. Electronic address: [email protected].

PMID: 32249117
DOI: 10.1016/j.bmcl.2020.127141

Abstract

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.

Keywords: Absolute configuration; Immunomodulatory effect; Monophosphate ester; OPA derivatization protocol; S1P(1).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chromatography, High Pressure Liquid
Circular Dichroism
Half-Life
Immunologic Factors / chemical synthesis*
Immunologic Factors / metabolism
Phosphorylation
Prodrugs / chemistry*
Prodrugs / pharmacokinetics
Rats
Sphingosine-1-Phosphate Receptors / agonists*
Sphingosine-1-Phosphate Receptors / metabolism
Stereoisomerism
Structure-Activity Relationship

Substances

Immunologic Factors
Prodrugs
Sphingosine-1-Phosphate Receptors