Prodrugs of N-dicarboximide derivatives of the rat selective toxicant norbormide
| Autor: | Morgan Jay-Smith, Olivia Laita, Sergio Bova, Margaret A. Brimble, Jan Knauf, Maurizio Cavalli, Darwin S. Linthicum, David Rennison, Brian Hopkins, Daniel Conole |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
Taste Clinical Biochemistry Pharmaceutical Science Pharmacology Imides Biochemistry Norbormide Rats Sprague-Dawley chemistry.chemical_compound In vivo Drug Discovery Animals Prodrugs Rodenticide Rats Wistar Molecular Biology Aorta chemistry.chemical_classification Hydrolysis Organic Chemistry Prodrug Norbornanes In vitro Rats Enzyme Liver chemistry Molecular Medicine Muscle Contraction Toxicant |
| Zdroj: | Bioorganic & Medicinal Chemistry. 21:5886-5899 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2013.06.071 |
| Popis: | Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either its unpleasant 'taste' or rapid onset of effects. A series of NRB-derived prodrugs were prepared in an effort to 'mask' this acute response. Their synthesis and biological evaluation (in vitro vasoconstrictory activity, in vitro hydrolytic and enzymatic stability and lethality/palatability in vivo) is described. Prodrug 2 displayed the most promising profile with respect to a delay in the onset of symptoms and was subsequently demonstrated to be significantly more palatable to rats. Moreover, prodrug 25 was found to be largely accepted by rats in a choice trial, resulting in high mortality. |
| Databáze: | OpenAIRE |
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