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Discovery of soft-drug topical tool modulators of Sphingosine-1-phosphate Receptor 1 (S1PR1)

Bell, Mark, Foley, David, Naylor, Claire, Wood, Gavin, Robinson, Colin, Riley, Jennifer, Epemolu, Ola, Ellis, Lucy, Scullion, Paul, Shishikura, Yoko, Osuna-Cabello, Maria, Ferguson, Liam, Pinto, Erika, Fletcher, Daniel, Katz, Elad, McLean, W. H. Irwin, Wyatt, Paul, Read, Kevin D and Woodland, Andrew 2019. Discovery of soft-drug topical tool modulators of Sphingosine-1-phosphate Receptor 1 (S1PR1). ACS Medicinal Chemistry Letters 10 (3) , pp. 341-347. 10.1021/acsmedchemlett.8b00616

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Chemical Society
ISSN: 1948-5875
Date of First Compliant Deposit: 20 February 2019
Date of Acceptance: 14 February 2019
Last Modified: 10 Mar 2020 19:59

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