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Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists

Peroxisome proliferator-activated receptor γ (PPARγ) is a well-known target for thiazolidinedione antidiabetic drugs. In this paper, we present the synthesis and biological evaluation of a series of dihydropyrano[2,3-c]pyrazole derivatives as a novel family of PPARγ partial agonists. Two analogues w...

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Autores principales: Qvortrup, Katrine, Jensen, Jakob F., Sørensen, Mikael S., Kouskoumvekaki, Irene, Petersen, Rasmus K., Taboureau, Olivier, Kristiansen, Karsten, Nielsen, Thomas E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330453/
https://www.ncbi.nlm.nih.gov/pubmed/28245241
http://dx.doi.org/10.1371/journal.pone.0162642
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author Qvortrup, Katrine
Jensen, Jakob F.
Sørensen, Mikael S.
Kouskoumvekaki, Irene
Petersen, Rasmus K.
Taboureau, Olivier
Kristiansen, Karsten
Nielsen, Thomas E.
author_facet Qvortrup, Katrine
Jensen, Jakob F.
Sørensen, Mikael S.
Kouskoumvekaki, Irene
Petersen, Rasmus K.
Taboureau, Olivier
Kristiansen, Karsten
Nielsen, Thomas E.
author_sort Qvortrup, Katrine
collection PubMed
description Peroxisome proliferator-activated receptor γ (PPARγ) is a well-known target for thiazolidinedione antidiabetic drugs. In this paper, we present the synthesis and biological evaluation of a series of dihydropyrano[2,3-c]pyrazole derivatives as a novel family of PPARγ partial agonists. Two analogues were found to display high affinity for PPARγ with potencies in the micro molar range. Both of these hits were selective against PPARγ, since no activity was measured when tested against PPARα, PPARδ and RXRα. In addition, a novel modelling approach based on multiple individual flexible alignments was developed for the identification of ligand binding interactions in PPARγ. In combination with cell-based transactivation experiments, the flexible alignment model provides an excellent analytical tool to evaluate and visualize the effect of ligand chemical structure with respect to receptor binding mode and biological activity.
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spelling pubmed-53304532017-03-09 Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists Qvortrup, Katrine Jensen, Jakob F. Sørensen, Mikael S. Kouskoumvekaki, Irene Petersen, Rasmus K. Taboureau, Olivier Kristiansen, Karsten Nielsen, Thomas E. PLoS One Research Article Peroxisome proliferator-activated receptor γ (PPARγ) is a well-known target for thiazolidinedione antidiabetic drugs. In this paper, we present the synthesis and biological evaluation of a series of dihydropyrano[2,3-c]pyrazole derivatives as a novel family of PPARγ partial agonists. Two analogues were found to display high affinity for PPARγ with potencies in the micro molar range. Both of these hits were selective against PPARγ, since no activity was measured when tested against PPARα, PPARδ and RXRα. In addition, a novel modelling approach based on multiple individual flexible alignments was developed for the identification of ligand binding interactions in PPARγ. In combination with cell-based transactivation experiments, the flexible alignment model provides an excellent analytical tool to evaluate and visualize the effect of ligand chemical structure with respect to receptor binding mode and biological activity. Public Library of Science 2017-02-28 /pmc/articles/PMC5330453/ /pubmed/28245241 http://dx.doi.org/10.1371/journal.pone.0162642 Text en © 2017 Qvortrup et al 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 author and source are credited.
spellingShingle Research Article
Qvortrup, Katrine
Jensen, Jakob F.
Sørensen, Mikael S.
Kouskoumvekaki, Irene
Petersen, Rasmus K.
Taboureau, Olivier
Kristiansen, Karsten
Nielsen, Thomas E.
Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists
title Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists
title_full Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists
title_fullStr Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists
title_full_unstemmed Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists
title_short Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists
title_sort synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of pparγ partial agonists
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330453/
https://www.ncbi.nlm.nih.gov/pubmed/28245241
http://dx.doi.org/10.1371/journal.pone.0162642
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