Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure

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) inhibit...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science Ltd 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376317/
https://www.ncbi.nlm.nih.gov/pubmed/30616904
http://dx.doi.org/10.1016/j.bmcl.2018.12.066
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author 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.
author_facet 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.
author_sort Acton, Ben
collection PubMed
description 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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spelling pubmed-63763172019-02-26 Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure 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. Bioorg Med Chem Lett Article 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. Elsevier Science Ltd 2019-02-15 /pmc/articles/PMC6376317/ /pubmed/30616904 http://dx.doi.org/10.1016/j.bmcl.2018.12.066 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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.
Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure
title Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure
title_full Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure
title_fullStr Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure
title_full_unstemmed Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure
title_short Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure
title_sort fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – a cautionary disclosure
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376317/
https://www.ncbi.nlm.nih.gov/pubmed/30616904
http://dx.doi.org/10.1016/j.bmcl.2018.12.066
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