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Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure |
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| Authors: | Jaye Michael C Krawiec John A Campobasso Nino Smallwood Angela Qiu Chunyan Lu Quinn Kerrigan John J De Los Frailes Alvaro Maite Laffitte Bryan Liu Wu-Schyong Marino Joseph P Meyer Craig R Nichols Jason A Parks Derek J Perez Paloma Sarov-Blat Lea Seepersaud Sheila D Steplewski Klaudia M Thompson Scott K Wang Ping Watson Mike A Webb Christine L Haigh David Caravella Justin A Macphee Colin H Willson Timothy M Collins Jon L |
| Affiliation: | GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA. |
| Abstract: | 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. |
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