Short communication
Qiong Xiao, Minwan Hu, Si Chen, Yifan Tang, Zeyu Shi, Jing Jin, Jinping Hu, Ping Xie, Dali Yin. Design and synthesis of selective sphingosine-1-phosphate receptor 1 agonists with increased phosphorylation rates[J]. Acta Pharmaceutica Sinica B, 2020, 10(6): 1134-1142

Design and synthesis of selective sphingosine-1-phosphate receptor 1 agonists with increased phosphorylation rates
Qiong Xiaoa, Minwan Hub, Si Chena, Yifan Tangc, Zeyu Shib, Jing Jind, Jinping Hub, Ping Xiea, Dali Yina
a 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;
b 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;
c Beijing Union Pharmaceutical Factory, Beijing 102600, China;
d 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
Abstract:
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.
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Received: 2019-09-05     Revised: 2019-10-08
DOI: 10.1016/j.apsb.2019.11.005
Funds: This work was 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), and Disciplines construction project (No. 201920200802, China).
Corresponding author: Jinping Hu, Ping Xie, Dali Yin     Email:hujp@imm.ac.cn;xp@imm.ac.cn;yindali@imm.ac.cn
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References:
1. Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, et al. Fingolimod (FTY720):discovery and development of an oral drug to treat multiple sclerosis.Nat RevDrugDiscov 2010;9:883-97.
2. Albert R, Hinterding K, Brinkmann V, Guerini D, Muller-Hartwieg C, Knecht H, et al. Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer. J Med Chem 2005;48:5373-7.
3. Billich A, Bornancin F, Dévay P, Mechtcheriakova D, Urtz N, Baumruker T. Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem 2003;278:47408-15.
4. Allende ML, Dreier JL, Mandala S, Proia RL. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem 2004;279:15396-401.
5. Sykes DA, Riddy DM, Stamp C, Bradley ME, McGuiness N, Sattikar A, et al. Investigating the molecular mechanisms through which FTY720-P causes persistent S1P1 receptor internalization. Br J Pharmacol 2014;171:4797-807.
6. Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 2007;316:295-8.
7. Fujino M, Funeshima N, Kitazawa Y, Kimura H, Amemiya H, Suzuki S, et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 2003;305:70-7.
8. Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006;355:1124-40.
9. O'Connor P, Comi G, Montalban X, Antel J, Radue EW, de Vera A, et al. Oral fingolimod (FTY720) in multiple sclerosis:two-year results of a phase II extension study. Neurology 2009;72:73-9.
10. Fyrst H, Saba JD. An update on sphingosine-1-phosphate and other sphingolipid mediators. Nat Chem Biol 2010;6:489-97.
11. Marciniaka A, Campb SM, Garciab JGN, Polta R. An update on sphingosine-1-phosphate receptor 1 modulators. Bioorg Med Chem Lett 2018;28:3585-91.
12. Tian Y, Jin J, Wang X, Han W, Li G, Zhou W, et al. Design, synthesis and docking-based 3D-QSAR study of novel 2-substituted 2-aminopropane-1,3-diols as potent and selective agonists of sphingosine-1-phosphate 1 (S1P1) receptor. Med Chem Commun 2013;4:1267-74.
13. Xiao Q, Jin J, Wang X, Hu J, Xi M, Tian Y, et al. Synthesis, identification, and biological activity of metabolites of two novel selective S1P1 agonists. Bioorg Med Chem 2016;24:2273-9.
14. Jin J, Xue N, Liu Y, Fu R, Wang M, Ji M, et al. A novel S1P1 modulator IMMH002 ameliorates psoriasis in multiple animal models. Acta Pharm Sin B 2020;10:276-88.
15. Mi J, Zhao M, Yang S, Yang S, Jin J, Wang X, et al. Pharmacokinetics of H002, a novel S1PR1 modulator, and its metabolites in rat blood using liquid chromatography-tandem mass spectrometry. Acta Pharm Sin B 2016;6:576-83.
16. Deng H, Bernier SG, Doyle E, Lorusso J, Morgan BA, Westlin WF, et al. Discovery of clinical candidate GSK1842799 as a selective S1P1 receptor agonist (prodrug) for multiple sclerosis. ACS Med Chem Lett 2013;4:942-7.
17. Ksiązek M, Chacińska M, Chabowski A, Baranowski M. Sources, metabolism, and regulation of circulating sphingosine-1-phosphate. J Lipid Res 2015;56:1271-81.
18. Vogt H, Vanderheiden S, Braese S. Proline-catalyzed asymmetric amination of a,a-disubstituted aldehydes:synthesis of configurationally stable enantioenriched a-aminoaldehydes. Chem Commum 2003;35:2448-9.
19. Fu J, Yang Q, Wang Q, Ming J, Wang F, Xu X, et al. Enantioselective a-amination of branched aldehydes promoted by simple chiral primary amino acids. J Org Chem 2011;76:4661-4.
20. Tsuji T, Suzuki K, Nakamura T, Nishi T. Synthesis of a chiral phosphonium salt for the preparation of a-substituted alaninol derivatives. Tetrahedron 2014;70:5234-41.
21. Sibi MP, Rutherford D, Paul AR, Li B. Investigations of a nucleophilic alaninol synthon derived from serine. J Am Chem Soc 1999;121:7509-16.
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