Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure. Issue 4 (15th February 2019)

• Record Type: Journal Article
• Authors: Acton, Ben; Small, Helen F.; Smith, Kate M.; McGonagle, Alison; Stowell, Alexandra I.J.; James, Dominic I.; Hamilton, Niall M.; Hamilton, Nicola; Hitchin, James R.; Hutton, Colin P.; Waddell, Ian D.; Ogilvie, Donald J.; Jordan, Allan M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 4(2019)
• Page Start: 560
• Page End: 562
• Publication Date: 2019-02-15
• Subjects: GI gastrointestinal -- PARG poly-ADP ribose glycohydrolase -- PK Pharmacokinetics; JXROTDVXUCWZRJ-UHFFFAOYSA-N -- URAVBHWPUHHWPE-UHFFFAOYSA-N -- ZOFHEKCMFGZPBH-UHFFFAOYSA-N -- NNBIAMICHJGJJL-UHFFFAOYSA-N -- YPJSTCOAXTXCOC-UHFFFAOYSA-N -- PHMBUKPLTWFJTD-UHFFFAOYSA-N -- YIIIUBIPEMDTEA-FIBGUPNXSA-N -- VDNPAHSYCDBDLA-UHFFFAOYSA-N -- HUMXMXKZASBHLD-UHFFFAOYSA-N -- VQYIPERYJDIKMW-UHFFFAOYSA-N -- DCNRZHQYMXKMBD-UHFFFAOYSA-N -- KFMMUYOIQZVTHD-UHFFFAOYSA-N -- YIIIUBIPEMDTEA-UHFFFAOYSA-N; Ataxia -- Animal welfare -- Toxicophore; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.12.066
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.