Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores - a cautionary disclosure
Small, Helen F
Smith, Kate M
McGonagle, Alison E
Stowell, Alexandra I
James, Dominic I
Hamilton, Nial M
Hamilton, Nicola S
Hitchin, James R
Hutton, Colin P
Waddell, Ian D
Ogilvie, Donald J
Jordan, Allan M
AffiliationDrug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK
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AbstractFluorination 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.
CitationActon B, Small HF, Smith KM, McGonagle A, Stowell AIJ, James DI, et al. Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores - a cautionary disclosure. Bioorg Med Chem Lett. 2019 Jan 2.
JournalBioorganic and Medicinal Chemistry Letters
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