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Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [(18)F] PET tracer

A series of novel derivatives exhibiting high affinity and selectivity towards the COX-2 enzyme in the (aza) indazole series was developed. A short synthetic route involving a bromination/arylation sequence under microwave irradiation and direct C–H activation were established in the indazole and az...

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Autores principales: Elie, Jonathan, Vercouillie, Johnny, Arlicot, Nicolas, Lemaire, Lucas, Bidault, Rudy, Bodard, Sylvie, Hosselet, Christel, Deloye, Jean-Bernard, Chalon, Sylvie, Emond, Patrick, Guilloteau, Denis, Buron, Frédéric, Routier, Sylvain
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211253/
https://www.ncbi.nlm.nih.gov/pubmed/30362376
http://dx.doi.org/10.1080/14756366.2018.1501043
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author Elie, Jonathan
Vercouillie, Johnny
Arlicot, Nicolas
Lemaire, Lucas
Bidault, Rudy
Bodard, Sylvie
Hosselet, Christel
Deloye, Jean-Bernard
Chalon, Sylvie
Emond, Patrick
Guilloteau, Denis
Buron, Frédéric
Routier, Sylvain
author_facet Elie, Jonathan
Vercouillie, Johnny
Arlicot, Nicolas
Lemaire, Lucas
Bidault, Rudy
Bodard, Sylvie
Hosselet, Christel
Deloye, Jean-Bernard
Chalon, Sylvie
Emond, Patrick
Guilloteau, Denis
Buron, Frédéric
Routier, Sylvain
author_sort Elie, Jonathan
collection PubMed
description A series of novel derivatives exhibiting high affinity and selectivity towards the COX-2 enzyme in the (aza) indazole series was developed. A short synthetic route involving a bromination/arylation sequence under microwave irradiation and direct C–H activation were established in the indazole and azaindazole series respectively. In vitro assays were conducted and structural modifications were carried out on these scaffolds to furnish compound 16 which exhibited effective COX-2 inhibitory activity, with IC(50) values of 0.409 µM and an excellent selectivity versus COX-1. Radiolabeling of this most potent derivative [(18)F]16 was achieved after boron ester release and the tracer was evaluated in vivo in a rat model of neuroinflammation. All chemistry, radiochemistry and biological experimental data are discussed.
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spelling pubmed-62112532018-11-05 Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [(18)F] PET tracer Elie, Jonathan Vercouillie, Johnny Arlicot, Nicolas Lemaire, Lucas Bidault, Rudy Bodard, Sylvie Hosselet, Christel Deloye, Jean-Bernard Chalon, Sylvie Emond, Patrick Guilloteau, Denis Buron, Frédéric Routier, Sylvain J Enzyme Inhib Med Chem Research Paper A series of novel derivatives exhibiting high affinity and selectivity towards the COX-2 enzyme in the (aza) indazole series was developed. A short synthetic route involving a bromination/arylation sequence under microwave irradiation and direct C–H activation were established in the indazole and azaindazole series respectively. In vitro assays were conducted and structural modifications were carried out on these scaffolds to furnish compound 16 which exhibited effective COX-2 inhibitory activity, with IC(50) values of 0.409 µM and an excellent selectivity versus COX-1. Radiolabeling of this most potent derivative [(18)F]16 was achieved after boron ester release and the tracer was evaluated in vivo in a rat model of neuroinflammation. All chemistry, radiochemistry and biological experimental data are discussed. Taylor & Francis 2018-10-26 /pmc/articles/PMC6211253/ /pubmed/30362376 http://dx.doi.org/10.1080/14756366.2018.1501043 Text en © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Elie, Jonathan
Vercouillie, Johnny
Arlicot, Nicolas
Lemaire, Lucas
Bidault, Rudy
Bodard, Sylvie
Hosselet, Christel
Deloye, Jean-Bernard
Chalon, Sylvie
Emond, Patrick
Guilloteau, Denis
Buron, Frédéric
Routier, Sylvain
Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [(18)F] PET tracer
title Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [(18)F] PET tracer
title_full Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [(18)F] PET tracer
title_fullStr Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [(18)F] PET tracer
title_full_unstemmed Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [(18)F] PET tracer
title_short Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [(18)F] PET tracer
title_sort design of selective cox-2 inhibitors in the (aza)indazole series. chemistry, in vitro studies, radiochemistry and evaluations in rats of a [(18)f] pet tracer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211253/
https://www.ncbi.nlm.nih.gov/pubmed/30362376
http://dx.doi.org/10.1080/14756366.2018.1501043
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