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Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1
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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Science Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185871/ https://www.ncbi.nlm.nih.gov/pubmed/30143424 http://dx.doi.org/10.1016/j.bmcl.2018.07.044 |
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author | Bell, Mark Foley, David Naylor, Claire Robinson, Colin Riley, Jennifer Epemolu, Ola Scullion, Paul Shishikura, Yoko Katz, Elad McLean, W.H. Irwin Wyatt, Paul Read, Kevin D. Woodland, Andrew |
author_facet | Bell, Mark Foley, David Naylor, Claire Robinson, Colin Riley, Jennifer Epemolu, Ola Scullion, Paul Shishikura, Yoko Katz, Elad McLean, W.H. Irwin Wyatt, Paul Read, Kevin D. Woodland, Andrew |
author_sort | Bell, Mark |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6185871 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Elsevier Science Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-61858712018-10-15 Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1 Bell, Mark Foley, David Naylor, Claire Robinson, Colin Riley, Jennifer Epemolu, Ola Scullion, Paul Shishikura, Yoko Katz, Elad McLean, W.H. Irwin Wyatt, Paul Read, Kevin D. Woodland, Andrew Bioorg Med Chem Lett Article 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. Elsevier Science Ltd 2018-10-15 /pmc/articles/PMC6185871/ /pubmed/30143424 http://dx.doi.org/10.1016/j.bmcl.2018.07.044 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bell, Mark Foley, David Naylor, Claire Robinson, Colin Riley, Jennifer Epemolu, Ola Scullion, Paul Shishikura, Yoko Katz, Elad McLean, W.H. Irwin Wyatt, Paul Read, Kevin D. Woodland, Andrew Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1 |
title | Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1 |
title_full | Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1 |
title_fullStr | Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1 |
title_full_unstemmed | Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1 |
title_short | Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1 |
title_sort | discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185871/ https://www.ncbi.nlm.nih.gov/pubmed/30143424 http://dx.doi.org/10.1016/j.bmcl.2018.07.044 |
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