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)

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Abstract

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
Volume10
Issue number3
Early online date14 Feb 2019
DOIs
Publication statusPublished - 14 Mar 2019

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Lysosphingolipid Receptors
Drug Discovery
Modulators
Skin
Pharmaceutical Preparations
Animal Disease Models
Phenols
Drug Design
Phenol
Skin Diseases
Enzymatic hydrolysis
Esters
Hydrolysis
Research Personnel
Animals
Blood

Keywords

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

Cite this

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title = "Discovery of Soft-Drug Topical Tool Modulators of Sphingosine-1-phosphate Receptor 1 (S1PR1)",
abstract = "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.",
keywords = "Plasma stability, S1PR, Soft-drug, Topical tool compound",
author = "Mark Bell and David Foley and Claire Naylor and Gavin Wood and Colin Robinson and Jennifer Riley and Rafiu Epemolu and Lucy Ellis and Stanley Scullion and Yoko Shishikura and Maria Osuna-Cabello and Liam Ferguson and Erika Pinto and Daniel Fletcher and Elad Katz and William McLean and Paul Wyatt and Kevin Read and Christopher Woodland",
note = "This work was supported by the Wellcome Trust [098439/Z/12/Z].",
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doi = "10.1021/acsmedchemlett.8b00616",
language = "English",
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T1 - Discovery of Soft-Drug Topical Tool Modulators of Sphingosine-1-phosphate Receptor 1 (S1PR1)

AU - Bell, Mark

AU - Foley, David

AU - Naylor, Claire

AU - Wood, Gavin

AU - Robinson, Colin

AU - Riley, Jennifer

AU - Epemolu, Rafiu

AU - Ellis, Lucy

AU - Scullion, Stanley

AU - Shishikura, Yoko

AU - Osuna-Cabello, Maria

AU - Ferguson, Liam

AU - Pinto, Erika

AU - Fletcher, Daniel

AU - Katz, Elad

AU - McLean, William

AU - Wyatt, Paul

AU - Read, Kevin

AU - Woodland, Christopher

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PY - 2019/3/14

Y1 - 2019/3/14

N2 - 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.

AB - 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.

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