Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure.

Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure.

Journal of medicinal chemistry (2005-08-19)

Michael C Jaye, John A Krawiec, Nino Campobasso, Angela Smallwood, Chunyan Qiu, Quinn Lu, John J Kerrigan, Maite De Los Frailes Alvaro, Bryan Laffitte, Wu-Schyong Liu, Joseph P Marino, Craig R Meyer, Jason A Nichols, Derek J Parks, Paloma Perez, Lea Sarov-Blat, Sheila D Seepersaud, Klaudia M Steplewski, Scott K Thompson, Ping Wang, Mike A Watson, Christine L Webb, David Haigh, Justin A Caravella, Colin H Macphee, Timothy M Willson, Jon L Collins

PMID16107141

摘要

Substituted 3-(phenylamino)-1H-pyrrole-2,5-diones were identified from a high throughput screen as inducers of human ATP binding cassette transporter A1 expression. Mechanism of action studies led to the identification of GSK3987 as an LXR ligand. GSK3987 recruits the steroid receptor coactivator-1 to human LXRalpha and LXRbeta with EC(50)s of 40 nM, profiles as an LXR agonist in functional assays, and activates LXR though a mechanism that is similar to first generation LXR agonists.