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Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores - A cautionary disclosure
Ben Acton1, Helen F Small1, Kate M Smith1
1Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK.
Abstract:
Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve in vivo half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected in vivo toxicity which was attributed to this single-atom modification.
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