Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1

Bioorganic & Medicinal Chemistry Letters
Mark BellAndrew Woodland

Abstract

The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.

Citations

Feb 6, 2020·European Journal of Immunology·Christian SchusterAndreas Weigert
Feb 11, 2020·Frontiers in Neuroscience·Marco TjakraGuixue Wang
Oct 15, 2020·International Journal of Molecular Sciences·Michio Tokuyama, Tomotaka Mabuchi
Mar 23, 2021·JCI Insight·Laura M Cobb, Michael R Verneris
Jul 10, 2021·Biologics : Targets & Therapy·Francesco BellinatoGiampiero Girolomoni
Mar 21, 2019·ACS Medicinal Chemistry Letters·Mark BellAndrew Woodland

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