Design and synthesis of analogues of the sphingosine-1-phosphate receptor 1 agonist IMMH001 with improved phosphorylation rate in human blood

Qiong Xiao; Minwan Hu; Si Chen; Zeyu Shi; Jinping Hu; Ping Xie; Dali Yin

doi:10.1016/j.bmc.2020.115722

Design and synthesis of analogues of the sphingosine-1-phosphate receptor 1 agonist IMMH001 with improved phosphorylation rate in human blood

Bioorg Med Chem. 2020 Nov 1;28(21):115722. doi: 10.1016/j.bmc.2020.115722. Epub 2020 Aug 26.

Authors

Qiong Xiao¹, Minwan Hu², Si Chen¹, Zeyu Shi¹, Jinping Hu³, Ping Xie⁴, 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 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.
³ 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. Electronic address: hujp@imm.ac.cn.
⁴ 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: xp@imm.ac.cn.
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: yindali@imm.ac.cn.

PMID: 33065444
DOI: 10.1016/j.bmc.2020.115722

Abstract

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.

Keywords: Modular approach; Molecular design; Phosphorylation rate; Prodrug; S1P(1) agonist.

Publication types

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

MeSH terms

Animals
Benzaldehydes / chemistry
Benzaldehydes / metabolism
Benzaldehydes / pharmacology
Binding Sites
Biphenyl Compounds / chemistry
Biphenyl Compounds / metabolism
Biphenyl Compounds / pharmacology
Catalytic Domain
Drug Design*
Humans
Ligands
Phosphorylation / drug effects
Prodrugs / chemical synthesis*
Prodrugs / metabolism
Prodrugs / pharmacology
Rats
Sphingosine-1-Phosphate Receptors / agonists*
Sphingosine-1-Phosphate Receptors / metabolism

Substances

Benzaldehydes
Biphenyl Compounds
Ligands
Prodrugs
Sphingosine-1-Phosphate Receptors
diphenyl
benzaldehyde