Discovery of Soft-Drug Topical Tool Modulators of Sphingosine-1-phosphate Receptor 1 (S1PR1)

Mark Bell (Lead / Corresponding author), David Foley, Claire Naylor, Gavin Wood, Colin Robinson, Jennifer Riley, Rafiu Epemolu, Lucy Ellis, Stanley Scullion, Yoko Shishikura, Maria Osuna-Cabello, Liam Ferguson, Erika Pinto, Daniel Fletcher, Elad Katz, William McLean, Paul Wyatt, Kevin Read, Christopher Woodland (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
251 Downloads (Pure)


In order to study the role of S1PRs in inflammatory skin disease, S1PR modulators are dosed orally and topically in animal models of disease. The topical application of S1PR modulators in these models may, however, lead to systemic drug concentrations, which can complicate interpretation of the observed effects. We set out to design soft drug S1PR modulators as topical tool compounds to overcome this limitation. A fast follower approach starting from the drug ponesimod allowed the rapid development of an active phenolic series of soft drugs. The phenols were, however, chemically unstable. Protecting the phenol as an ester removed the instability and provided a compound that is converted by enzymatic hydrolysis in the skin to the phenolic soft drug species. In simple formulations, topical dosing of these S1PR modulators to mice led to micromolar skin concentrations but no detectable blood concentrations. These topical tools will allow researchers to investigate the role of S1PR in skin, without involvement of systemic S1PR biology.
Original languageEnglish
Pages (from-to)341–347
Number of pages7
JournalACS Medicinal Chemistry Letters
Issue number3
Early online date14 Feb 2019
Publication statusPublished - 14 Mar 2019


  • Plasma stability
  • S1PR
  • Soft-drug
  • Topical tool compound

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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