Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

Journal Article · Thu Aug 12 00:00:00 EDT 2010 · J. Med. Chem.

DOI:https://doi.org/10.1021/jm901797p· OSTI ID:1002577

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 ^[1]

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1. GSKNC

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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE
• OSTI ID: 1002577
• Journal Information: J. Med. Chem., Vol. 53, Issue (8) ; 04, 2010; ISSN 0022-2623
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
AFFINITY
BIOLOGY
LIVER
PROBES
SULFONAMIDES
SYNTHESIS