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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC6128612?pdf=render |
| _version_ | 1811205783558291456 |
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| author | Dawn M George Raymond J Huntley Kevin Cusack David B Duignan Michael Hoemann Jacqueline Loud Regina Mario Terry Melim Kelly Mullen Gagandeep Somal Lu Wang Jeremy J Edmunds |
| author_facet | Dawn M George Raymond J Huntley Kevin Cusack David B Duignan Michael Hoemann Jacqueline Loud Regina Mario Terry Melim Kelly Mullen Gagandeep Somal Lu Wang Jeremy J Edmunds |
| author_sort | Dawn M George |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T03:36:07Z |
| format | Article |
| id | doaj.art-f9e4d7a1ef864cb18c1b355c36fdb091 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T03:36:07Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f9e4d7a1ef864cb18c1b355c36fdb0912022-12-22T03:49:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01139e020356710.1371/journal.pone.0203567Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors.Dawn M GeorgeRaymond J HuntleyKevin CusackDavid B DuignanMichael HoemannJacqueline LoudRegina MarioTerry MelimKelly MullenGagandeep SomalLu WangJeremy J EdmundsThe 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.http://europepmc.org/articles/PMC6128612?pdf=render |
| spellingShingle | Dawn M George Raymond J Huntley Kevin Cusack David B Duignan Michael Hoemann Jacqueline Loud Regina Mario Terry Melim Kelly Mullen Gagandeep Somal Lu Wang Jeremy J Edmunds Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC6128612?pdf=render |
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