Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors.

Abstract

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 13 Issue 9 Pg. e0203567 ( 2018) ISSN: 1932-6203 [Electronic] United States
• PMID: 30192846 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Csf1r protein, mouse
• Cyclodextrins
• Prodrugs
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
• Dextran Sulfate

Topics

• Animals
• Colitis (chemically induced, drug therapy, immunology)
• Colon (chemistry)
• Cyclodextrins (chemistry)
• Dextran Sulfate (adverse effects)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Female
• Macrophages (drug effects, metabolism)
• Mice
• Models, Molecular
• Molecular Structure
• Prodrugs (administration & dosage, chemical synthesis, chemistry, pharmacokinetics)
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor (antagonists & inhibitors)