Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
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
_version_ 1783353675907858432
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
work_keys_str_mv AT georgedawnm prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT huntleyraymondj prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT cusackkevin prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT duignandavidb prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT hoemannmichael prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT loudjacqueline prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT marioregina prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT melimterry prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT mullenkelly prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT somalgagandeep prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT wanglu prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors
AT edmundsjeremyj prodrugsforcolonrestricteddeliverydesignsynthesisandinvivoevaluationofcolonystimulatingfactor1receptorcsf1rinhibitors