Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity.

@article{Chao2008StructureguidedDO,
  title={Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity.},
  author={Esther Y H Chao and Justin A. Caravella and Mike A Watson and Nino Campobasso and Serena Ghisletti and Andrew N Billin and Cristin M. Galardi and Ping Wang and Bryan A. Laffitte and Marie A. Iannone and Bryan J Goodwin and J. F. A. Nichols and Derek J. Parks and Eugene L. Stewart and Robert W. Wiethe and Shawn P. Williams and Angela Smallwood and Kenneth H. Pearce and Christopher K. Glass and Timothy M Willson and William J. Zuercher and Jon L. Collins},
  journal={Journal of medicinal chemistry},
  year={2008},
  volume={51 18},
  pages={5758-65}
}
A cocrystal structure of T1317 (3) bound to hLXRbeta was utilized in the design of a series of substituted N-phenyl tertiary amines. Profiling in binding and functional assays led to the identification of LXR modulator GSK9772 ( 20) as a high-affinity LXRbeta ligand (IC 50 = 30 nM) that shows separation of anti-inflammatory and lipogenic activities in human macrophage and liver cell lines, respectively. A cocrystal structure of the structurally related analog 19 bound to LXRbeta reveals regions… CONTINUE READING

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