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J Med Chem. 2016 Apr 14;59(7):3264-71. doi: 10.1021/acs.jmedchem.5b02029. Epub 2016 Mar 29.

Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) β Agonist.

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Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.


This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor β (LXRβ) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRβ and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRβ with high affinity and to LXRα to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis.

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