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Substrate-Selective Inhibition of Cyclooxygenase-2: Development and Evaluation of Achiral Profen Probes
[Image: see text] Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work,...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2012
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441040/ https://www.ncbi.nlm.nih.gov/pubmed/22984634 http://dx.doi.org/10.1021/ml3001616 |
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author | Windsor, Matthew A. Hermanson, Daniel J. Kingsley, Philip J. Xu, Shu Crews, Brenda C. Ho, Winnie Keenan, Catherine M. Banerjee, Surajit Sharkey, Keith A. Marnett, Lawrence J. |
author_facet | Windsor, Matthew A. Hermanson, Daniel J. Kingsley, Philip J. Xu, Shu Crews, Brenda C. Ho, Winnie Keenan, Catherine M. Banerjee, Surajit Sharkey, Keith A. Marnett, Lawrence J. |
author_sort | Windsor, Matthew A. |
collection | PubMed |
description | [Image: see text] Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC(50) of 0.11 μM for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition. |
format | Online Article Text |
id | pubmed-3441040 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-34410402012-09-13 Substrate-Selective Inhibition of Cyclooxygenase-2: Development and Evaluation of Achiral Profen Probes Windsor, Matthew A. Hermanson, Daniel J. Kingsley, Philip J. Xu, Shu Crews, Brenda C. Ho, Winnie Keenan, Catherine M. Banerjee, Surajit Sharkey, Keith A. Marnett, Lawrence J. ACS Med Chem Lett [Image: see text] Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC(50) of 0.11 μM for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition. American Chemical Society 2012-08-15 /pmc/articles/PMC3441040/ /pubmed/22984634 http://dx.doi.org/10.1021/ml3001616 Text en Copyright © 2012 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) |
spellingShingle | Windsor, Matthew A. Hermanson, Daniel J. Kingsley, Philip J. Xu, Shu Crews, Brenda C. Ho, Winnie Keenan, Catherine M. Banerjee, Surajit Sharkey, Keith A. Marnett, Lawrence J. Substrate-Selective Inhibition of Cyclooxygenase-2: Development and Evaluation of Achiral Profen Probes |
title | Substrate-Selective Inhibition
of Cyclooxygenase-2:
Development and Evaluation of Achiral Profen Probes |
title_full | Substrate-Selective Inhibition
of Cyclooxygenase-2:
Development and Evaluation of Achiral Profen Probes |
title_fullStr | Substrate-Selective Inhibition
of Cyclooxygenase-2:
Development and Evaluation of Achiral Profen Probes |
title_full_unstemmed | Substrate-Selective Inhibition
of Cyclooxygenase-2:
Development and Evaluation of Achiral Profen Probes |
title_short | Substrate-Selective Inhibition
of Cyclooxygenase-2:
Development and Evaluation of Achiral Profen Probes |
title_sort | substrate-selective inhibition
of cyclooxygenase-2:
development and evaluation of achiral profen probes |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441040/ https://www.ncbi.nlm.nih.gov/pubmed/22984634 http://dx.doi.org/10.1021/ml3001616 |
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