Design and synthesis of selective sphingosine-1-phosphate receptor 1 agonists with increased phosphorylation rates  

作　　者：Qiong Xiao Minwan Hu Si Chen Yifan Tang Zeyu Shi Jing Jin Jinping Hu Ping Xie Dali Yin 

机构地区：[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,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,Chinese Academy of Medical Sciences,Beijing 100050,China [3]Beijing Union Pharmaceutical Factory,Beijing 102600,China [4]Department of Pharmacology,State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing 100050,China

出　　处：《Acta Pharmaceutica Sinica B》2020年第6期1134-1142,共9页药学学报（英文版）

基　　金：financially supported by the Drug Innovation Major Project(No.2018ZX09711001-005-012,China);National Key R&D Program of China(No.2018YFC1706403);CAMS Innovation Fund for Medical Sciences(No.2016-I2M-2-002,China);Disciplines construction project(No.201920200802,China)

摘　　要：FTY720 and IMMH002,prodrugs for sphingosine-1-phosphate receptor 1(S1P1)agonists,show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats.In this study,FTY720 or IMMH002 analogues(21-24)were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms.Target compounds were synthesized via a convergent route using the key and optically pure building block 9,which was first synthesized via asymmetrically catalyzed amination.The phosphorylation rates of these analogues in rat or human blood were compared.The new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the parent compound,whereas compound 23 showed improvements in rats,but not in humans.In pharmacokinetics studies of rats,compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and IMMH002.Thus,our study not only yielded new compounds with therapeutic potential,but also showed species differences between rats and humans in response to the structural modifications,which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic.

关 键 词：S1P1 agonist PRODRUG Catalytic amination Phosphate formation rate LYMPHOCYTE 

分 类 号：R914[医药卫生—药物化学]