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

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.
Qiong Xiao 1,  Minwan Hu 2,  Si Chen 1,  Zeyu Shi 1,  Jinping Hu 3,  Ping Xie 4,  Dali Yin 5
Affiliations

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: [email protected].
  • 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: [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: 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.

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