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

Mark Bell (Lead / Corresponding author), David Foley, Claire Naylor, Colin Robinson, Jennifer Riley, Rafiu Epemolu, Stanley Scullion, Yoko Shishikura, Elad Katz, William McLean, Paul Wyatt, Kevin Read, Christopher Woodland (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
231 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)3255-3259
Number of pages5
JournalBioorganic & Medicinal Chemistry Letters
Volume28
Issue number19
Early online date30 Jul 2018
DOIs
Publication statusPublished - 15 Oct 2018

Keywords

  • Plasma stability
  • Psoriasis
  • S1PR1
  • Soft-drug
  • Topical

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