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Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors
The ability to restrict low molecular weight compounds to the gastrointestinal (GI) tract may enable an enhanced therapeutic index for molecular targets known to be associated with systemic toxicity. Using a triazolopyrazine CSF1R inhibitor scaffold, a broad range of prodrugs were synthesized and ev...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128612/ https://www.ncbi.nlm.nih.gov/pubmed/30192846 http://dx.doi.org/10.1371/journal.pone.0203567 |
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author | George, Dawn M. Huntley, Raymond J. Cusack, Kevin Duignan, David B. Hoemann, Michael Loud, Jacqueline Mario, Regina Melim, Terry Mullen, Kelly Somal, Gagandeep Wang, Lu Edmunds, Jeremy J. |
author_facet | George, Dawn M. Huntley, Raymond J. Cusack, Kevin Duignan, David B. Hoemann, Michael Loud, Jacqueline Mario, Regina Melim, Terry Mullen, Kelly Somal, Gagandeep Wang, Lu Edmunds, Jeremy J. |
author_sort | George, Dawn M. |
collection | PubMed |
description | The ability to restrict low molecular weight compounds to the gastrointestinal (GI) tract may enable an enhanced therapeutic index for molecular targets known to be associated with systemic toxicity. Using a triazolopyrazine CSF1R inhibitor scaffold, a broad range of prodrugs were synthesized and evaluated for enhanced delivery to the colon in mice. Subsequently, the preferred cyclodextrin prodrug moiety was appended to a number of CSF1R inhibitory active parent molecules, enabling GI-restricted delivery. Evaluation of a cyclodextrin prodrug in a dextran sodium sulfate (DSS)-induced mouse colitis model resulted in enhanced GI tissue levels of active parent. At a dose where no significant depletion of systemic monocytes were detected, the degree of pharmacodynamic effect–measured as reduction in macrophages in the colon–was inferior to that observed with a systemically available positive control. This suggests that a suitable therapeutic index cannot be achieved with CSF1R inhibition by using GI-restricted delivery in mice. However, these efforts provide a comprehensive frame-work in which to pursue additional gut-restricted delivery strategies for future GI targets. |
format | Online Article Text |
id | pubmed-6128612 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61286122018-09-15 Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors George, Dawn M. Huntley, Raymond J. Cusack, Kevin Duignan, David B. Hoemann, Michael Loud, Jacqueline Mario, Regina Melim, Terry Mullen, Kelly Somal, Gagandeep Wang, Lu Edmunds, Jeremy J. PLoS One Research Article The ability to restrict low molecular weight compounds to the gastrointestinal (GI) tract may enable an enhanced therapeutic index for molecular targets known to be associated with systemic toxicity. Using a triazolopyrazine CSF1R inhibitor scaffold, a broad range of prodrugs were synthesized and evaluated for enhanced delivery to the colon in mice. Subsequently, the preferred cyclodextrin prodrug moiety was appended to a number of CSF1R inhibitory active parent molecules, enabling GI-restricted delivery. Evaluation of a cyclodextrin prodrug in a dextran sodium sulfate (DSS)-induced mouse colitis model resulted in enhanced GI tissue levels of active parent. At a dose where no significant depletion of systemic monocytes were detected, the degree of pharmacodynamic effect–measured as reduction in macrophages in the colon–was inferior to that observed with a systemically available positive control. This suggests that a suitable therapeutic index cannot be achieved with CSF1R inhibition by using GI-restricted delivery in mice. However, these efforts provide a comprehensive frame-work in which to pursue additional gut-restricted delivery strategies for future GI targets. Public Library of Science 2018-09-07 /pmc/articles/PMC6128612/ /pubmed/30192846 http://dx.doi.org/10.1371/journal.pone.0203567 Text en © 2018 George et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article George, Dawn M. Huntley, Raymond J. Cusack, Kevin Duignan, David B. Hoemann, Michael Loud, Jacqueline Mario, Regina Melim, Terry Mullen, Kelly Somal, Gagandeep Wang, Lu Edmunds, Jeremy J. Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors |
title | Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors |
title_full | Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors |
title_fullStr | Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors |
title_full_unstemmed | Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors |
title_short | Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors |
title_sort | prodrugs for colon-restricted delivery: design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (csf1r) inhibitors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128612/ https://www.ncbi.nlm.nih.gov/pubmed/30192846 http://dx.doi.org/10.1371/journal.pone.0203567 |
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