title: Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists.
abstract: 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.
authors.affiliation: Department of Chemistry, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Katrine
authors.initials: K
authors.lastname: Qvortrup
authors.affiliation: Department of Chemistry, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Jakob F
authors.initials: JF
authors.lastname: Jensen
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Mikael S
authors.initials: MS
authors.lastname: Sørensen
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Irene
authors.initials: I
authors.lastname: Kouskoumvekaki
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, Denmark.
authors.forename: Rasmus K
authors.initials: RK
authors.lastname: Petersen
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Molécules Thérapeutiques in silico (MTi), Inserm UMR-S 973-Université Paris Diderot, Bat Lamarck A, 35 Rue Hélène Brion, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Taboureau
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: Department of Chemistry, Technical University of Denmark, Lyngby, Denmark.|Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011714:Pyrans / Q000138:chemical synthesis* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013816:Thermodynamics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D008024:Ligands; D047495:PPAR gamma; D011714:Pyrans; D011720:Pyrazoles; D014157:Transcription Factors; C000612181:dihydropyrano(2,3-c)pyrazole