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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,...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2012
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.
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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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