title: Synthesis of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists: Effects on the affinity and selectivity towards PPARβ/δ.
abstract: The covalent modification of peroxisome-proliferator activated receptor β/δ (PPARβ/δ) is part of the mode of action of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists such as GSK3787 and CC618. Herein, the synthesis and in vitro biological evaluation of a range of structural analogues of the two antagonists are reported. The new ligands demonstrate that an improvement in the selectivity of 5-trifluoromethyl-2-sulfonylpyridine antagonists towards PPARβ/δ is achievable at the expense of their immediate affinity for PPARβ/δ. However, their putatively covalent and irreversible mode of action may ensure their efficacy over time, as observed in time-resolved fluorescence resonance energy transfer (TR-FRET)-based ligand displacement assays.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, 0316 Oslo, Norway.
authors.forename: Åsmund
authors.initials: Å
authors.lastname: Kaupang
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, 0316 Oslo, Norway.
authors.forename: Eili Tranheim
authors.initials: ET
authors.lastname: Kase
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, 0316 Oslo, Norway.
authors.forename: Cecilie Xuan Trang
authors.initials: CX
authors.lastname: Vo
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, 0316 Oslo, Norway.
authors.forename: Marthe
authors.initials: M
authors.lastname: Amundsen
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, 0316 Oslo, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Vik
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, 0316 Oslo, Norway. Electronic address: t.v.hansen@farmasi.uio.no.
authors.forename: Trond Vidar
authors.initials: TV
authors.lastname: Hansen
mesh_terms: D004305:Dose-Response Relationship, Drug; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D015394:Molecular Structure; D047494:PPAR delta / Q000037:antagonists & inhibitors*; D048068:PPAR-beta / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000187:drug effects; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047494:PPAR delta; D048068:PPAR-beta; D011725:Pyridines; D013450:Sulfones
keywords: Antagonist; Covalent; PPAR; Selectivity; TR-FRET