Reversible oxidation/reduction steps in the metabolic degradation of the glycerol side chain of the S1P₁ modulator ponesimod

References

• Abele S, Bolli M, Schmidt G. 2008. New process for the preparation of 2-imino-thiazolidin-4-one derivatives. WO2008062376.
   Google Scholar
• Arnott JA, Planey SL. 2012. The influence of lipophilicity in drug discovery and design. Expert Opin Drug Discov. 7(10):863–875. doi: 10.1517/17460441.2012.714363.
   PubMed Web of Science ®Google Scholar
• Boehler M, Juif PE, Hoch M, Dingemanse J. 2017. Absolute bioavailability of ponesimod, a selective S1P1 receptor modulator, in healthy male subjects. Eur J Drug Metab Pharmacokinet. 42(1):129–134. doi: 10.1007/s13318-016-0325-6.
   PubMed Web of Science ®Google Scholar
• Bolli MH, Abele S, Binkert C, Bravo R, Buchmann S, Bur D, Gatfield J, Hess P, Kohl C, Mangold C, et al. 2010. 2-Imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. J Med Chem. 53(10):4198–4211. doi: 10.1021/jm100181s.
   PubMed Web of Science ®Google Scholar
• Brossard P, Scherz M, Halabi A, Maatouk H, Krause A, Dingemanse J. 2014. Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: favorable impact of dose up-titration. J Clin Pharmacol. 54(2):179–188. doi: 10.1002/jcph.244.
   PubMed Web of Science ®Google Scholar
• Brown BA, Kantesaria PP, McDevitt LM. 2007. Fingolimod: a novel immunosuppressant for multiple sclerosis. Ann Pharmacother. 41(10):1660–1668. doi: 10.1345/aph.1G424.
   PubMed Web of Science ®Google Scholar
• Chiba K. 2005. FTY720, a new class of immunomodulators, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther. 108(3):308–319. doi: 10.1016/j.pharmthera.2005.05.002.
   PubMed Web of Science ®Google Scholar
• D’ Ambrosio D, Freedman MS, Prinz J. 2016. Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. Ther Adv Chronic Dis. 7(1):18–33. doi: 10.1177/2040622315617354.
   PubMed Web of Science ®Google Scholar
• Dash RP, Rais R, Srinivas NR. 2018. Ponesimod, a selective sphingosine 1-phosphate (S1P1) receptor modulator for autoimmune diseases: review of clinical pharmacokinetics and drug disposition. Xenobiotica. 48(5):442–451. doi: 10.1080/00498254.2017.1329568.
   PubMed Web of Science ®Google Scholar
• Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, van Marle SP, Legangneux E, Borell H, James AD, et al. 2018. Metabolism and disposition of siponimod, a novel selective S1P1/S1P5 agonist, in healthy volunteers and in vitro identification of human cytochrome P450 enzymes involved in its oxidative metabolism. Drug Metab Dispos. 46(7):1001–1013. doi: 10.1124/dmd.117.079574.
   PubMed Web of Science ®Google Scholar
• Kappos L, Antel J, Comi G, Montalban X, O’ Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, FTY720 D2201 Study Group. 2006. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 355(11):1124–1140. doi: 10.1056/NEJMoa052643.
   PubMed Web of Science ®Google Scholar
• Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, Vermersch P, Arnold DL, Arnould S, Scherz T, et al. 2018. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomized, phase 3 study. Lancet. 391(10127):1263–1273. doi: 10.1016/S0140-6736(18)30475-6.
   PubMed Web of Science ®Google Scholar
• Marsolais D, Rosen H. 2009. Chemical modulators of sphingosine-1-phosphate receptors at barrier oriented therapeutic molecules. Nat Rev Drug Discov. 8(4):297–307. doi: 10.1038/nrd2356.
   PubMed Web of Science ®Google Scholar
• Neidlein R, Volland C, Kramer W. 1990. Spektroskopische Eigenschaften des partiellen beta-Agonisten Doxaminol (BM.10.188) und seiner Stoffwechselprodukte. Arch Pharm (Weinheim). 323(5):259–265. doi: 10.1002/ardp.19903230503.
   PubMedGoogle Scholar
• Reyes M, Hoch M, Brossard P, Wagner-Redeker W, Miraval T, Dingemanse J. 2015. Mass balance, pharmacokinetics, and metabolism of the selective S1P1 receptor modulator ponesimod in humans. Xenobiotica. 45(2):139–149. doi: 10.3109/00498254.2014.955832.
   PubMed Web of Science ®Google Scholar
• Rivera J, Proia RL, Olivera A. 2008. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol. 8(10):753–763. doi: 10.1038/nri2400.
   PubMed Web of Science ®Google Scholar
• Scott FL, Clemons B, Brooks J, Brahmachary E, Powell R, Dedman H, Desale HG, Timony GA, Martinborough E, Rosen H, et al. 2016. Ozanimod (RPC 1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br. J. Pharmacol. 173:1178–1192.
   Web of Science ®Google Scholar
• Tran JQ, Hartung JP, Olson AD, Mendzelevski B, Timony GA, Boehm MF, Peach RJ, Gujrathi S, Frohna PA. 2018. Cardiac safety of ozanimod, a novel sphingosine-1-phosphate receptor modulator: results of a thorough QT/QTc study. Clin Pharmacol Drug Dev. 7(3):263–276. doi: 10.1002/cpdd.383.
   PubMed Web of Science ®Google Scholar
• Van de Waterbeemd H, Smith DA, Jones BC. 2001. Lipophilicity in PK design: methyl, ethyl, futile. J Comput Aided Mol Des. 15(3):273–286. doi: 10.1023/a:1008192010023.
   PubMed Web of Science ®Google Scholar
• Vandenheuvel WJ, Smith JL, Silber RH. 1972. β-(2-Methoxyphenoxy)lactic acid, the major urinary metabolite of glyceryl guaiacolate in man. J Pharm Sci. 61(12):1997–1998. doi: 10.1002/jps.2600611226.
   PubMed Web of Science ®Google Scholar
• Zhang C, Wong S, Delarosa EM, Kenny JR, Halladay JS, Hop CE, Khojasteh-Bakht SC. 2009. Inhibitory properties of trapping agents: glutathione, potassium cyanide, and methoxylamine, against major human cytochrome P450 isoforms. Drug Metab Lett. 3(2):125–129. doi: 10.2174/187231209788654126.
   PubMedGoogle Scholar
• Zollinger M, Gschwind HP, Jin Y, Sayer C, Zécri F, Hartmann S. 2011. Absorption and disposition of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in healthy volunteers: a case of xenobiotic biotransformation following endogenous metabolic pathways. Drug Metab Dispos. 39(2):199–207. doi: 10.1124/dmd.110.035907.
   PubMed Web of Science ®Google Scholar