TY - JOUR
T1 - Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists
AU - Qvortrup, Katrine
AU - Jensen, Jakob Feldthusen
AU - Sørensen, Mikael S.
AU - Kouskoumvekaki, Eirini
AU - Petersen, Rasmus K.
AU - Taboureau, Olivier
AU - Kristiansen, Karsten
AU - Nielsen, Thomas Eiland
N1 - This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pone.0162642
DO - 10.1371/journal.pone.0162642
M3 - Journal article
C2 - 28245241
SN - 1932-6203
VL - 12
JO - P L o S One
JF - P L o S One
IS - 2
M1 - e0162642
ER -