Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores - a cautionary disclosure
Small, Helen F
Smith, Kate M
McGonagle, Alison E
Stowell, Alexandra I J
James, Dominic I
Hamilton, Niall 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
MetadataShow full item record
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
- Structures of the human poly (ADP-ribose) glycohydrolase catalytic domain confirm catalytic mechanism and explain inhibition by ADP-HPD derivatives.
- Authors: Tucker JA, Bennett N, Brassington C, Durant ST, Hassall G, Holdgate G, McAlister M, Nissink JW, Truman C, Watson M
- Issue date: 2012
- Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase.
- Authors: Dunstan MS, Barkauskaite E, Lafite P, Knezevic CE, Brassington A, Ahel M, Hergenrother PJ, Leys D, Ahel I
- Issue date: 2012 Jun 6
- Crystallographic and biochemical analysis of the mouse poly(ADP-ribose) glycohydrolase.
- Authors: Wang Z, Gagné JP, Poirier GG, Xu W
- Issue date: 2014
- New Insights into the Roles of NAD+-Poly(ADP-ribose) Metabolism and Poly(ADP-ribose) Glycohydrolase.
- Authors: Tanuma S, Sato A, Oyama T, Yoshimori A, Abe H, Uchiumi F
- Issue date: 2016
- Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides.
- Authors: Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ
- Issue date: 2018 Dec 13