Synthesis, identification, and biological activity of metabolites of two novel selective S1P1 agonists

Qiong Xiao; Jing Jin; Xiaojian Wang; Jinping Hu; Meiyang Xi; Yulin Tian; Dali Yin

doi:10.1016/j.bmc.2016.03.059

Synthesis, identification, and biological activity of metabolites of two novel selective S1P1 agonists

Bioorg Med Chem. 2016 May 15;24(10):2273-9. doi: 10.1016/j.bmc.2016.03.059. Epub 2016 Mar 31.

Authors

Qiong Xiao¹, Jing Jin², Xiaojian Wang¹, Jinping Hu², Meiyang Xi¹, Yulin Tian¹, Dali Yin³

Affiliations

¹ State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China; Department of Medicinal Chemistry, 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, PR China.
² State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
³ State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China; Department of Medicinal Chemistry, 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, PR China. Electronic address: yindali@imm.ac.cn.

PMID: 27068143
DOI: 10.1016/j.bmc.2016.03.059

Abstract

SYL927 and SYL930 are selective S1P1 agonists under preclinical development. However, during their pharmacokinetic studies we detected two metabolites in rat blood that were tentatively identified as monohydroxylated metabolites of SYL927 and SYL930 based on LC-MS/MS data. In this study, we designed and synthesized possible monohydroxylated products 6a-e and used them as references to confirm the structures of the two metabolites detected by LC-MS/MS. We also evaluated the in vitro and in vivo biological activities of these two metabolites.

Keywords: Metabolites; Monohydroxylated products; S1P(1).

Publication types

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

MeSH terms

Animals
Chromatography, Liquid
Fingolimod Hydrochloride / administration & dosage
Fingolimod Hydrochloride / analogs & derivatives*
Fingolimod Hydrochloride / pharmacology*
Hydroxylation
Immunosuppressive Agents / administration & dosage
Immunosuppressive Agents / chemistry*
Immunosuppressive Agents / pharmacology*
Lymphocyte Count
Lymphocytes / drug effects
Rats, Sprague-Dawley
Receptors, Lysosphingolipid / agonists*
Receptors, Lysosphingolipid / immunology
Tandem Mass Spectrometry

Substances

Immunosuppressive Agents
Receptors, Lysosphingolipid
Fingolimod Hydrochloride