Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 24, Issue 2, Pages 247-260Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.12.012
Keywords
PPAR; Antagonist; Covalent; Selectivity; TR-FRET
Funding
- School of Pharmacy
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The covalent modification of peroxisome-proliferator activated receptor beta/delta (PPAR beta/delta) is part of the mode of action of 5-trifluoromethyl-2-sulfonylpyridine PPAR beta/delta 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 PPAR beta/delta is achievable at the expense of their immediate affinity for PPAR beta/delta. 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. (c) 2015 Elsevier Ltd. All rights reserved.
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