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Title: Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

Abstract

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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. (GSKNC)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002577
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 53; Journal Issue: (8) ; 04, 2010; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; AFFINITY; BIOLOGY; LIVER; PROBES; SULFONAMIDES; SYNTHESIS

Citation Formats

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., and Willson, Timothy M. Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists. United States: N. p., 2010. Web. doi:10.1021/jm901797p.
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. Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists. United States. doi:10.1021/jm901797p.
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., and Willson, Timothy M. Thu . "Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists". United States. doi:10.1021/jm901797p.
@article{osti_1002577,
title = {Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists},
author = {Zuercher, William J. and Buckholz†, Richard G. and Campobasso, Nino and Collins, Jon L. and Galardi, Cristin M. and Gampe, Robert T. and Hyatt, Stephen M. and Merrihew, Susan L. and Moore, John T. and Oplinger, Jeffrey A. and Reid, Paul R. and Spearing, Paul K. and Stanley, Thomas B. and Stewart, Eugene L. and Willson, Timothy M.},
abstractNote = {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.},
doi = {10.1021/jm901797p},
journal = {J. Med. Chem.},
issn = {0022-2623},
number = (8) ; 04, 2010,
volume = 53,
place = {United States},
year = {2010},
month = {8}
}