Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding aff...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-04, Vol.53 (8), p.3412-3416
Main Authors: Zuercher, William J, Buckholz, Richard G, Campobasso, Nino, Collins, Jon L, Galardi, Cristin M, Gampe, Robert T, Hyatt, Stephen M, Merrihew, Susan L, Moore, John T, Oplinger, Jeffrey A, Reid, Paul R, Spearing, Paul K, Stanley, Thomas B, Stewart, Eugene L, Willson, Timothy M
Format: Article
Language:English
Subjects:
AFFINITY
Animals
BASIC BIOLOGICAL SCIENCES
BIOLOGY
Cell Line
Crystallography, X-Ray
GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
Haplorhini
Humans
LIVER
Liver X Receptors
Models, Molecular
Orphan Nuclear Receptors - antagonists & inhibitors
Orphan Nuclear Receptors - genetics
PROBES
Structure-Activity Relationship
SULFONAMIDES
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
SYNTHESIS
Transcriptional Activation - drug effects
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Description
Summary:Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm901797p