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

  • J Med Chem. 2016 Apr 14;59(7):3264-71. doi: 10.1021/acs.jmedchem.5b02029.
Yajun Zheng  1 ,  Linghang Zhuang  1 ,  Kristi Yi Fan  1 ,  Colin M Tice  1 ,  Wei Zhao  1 ,  Chengguo Dong  1 ,  Stephen D Lotesta  1 ,  Katerina Leftheris  1 ,  Peter R Lindblom  1 ,  Zhijie Liu  1 ,  Jun Shimada  1 ,  Paul B Noto  1 ,  Shi Meng  1 ,  Andrew Hardy  1 ,  Lamont Howard  1 ,  Paula Krosky  1 ,  Joan Guo  1 ,  Kerri Lipinski  1 ,  Geeta Kandpal  1 ,  Yuri Bukhtiyarov  1 ,  Yi Zhao  1 ,  Deepak Lala  1 ,  Rebecca Van Orden  1 ,  Jing Zhou  1 ,  Guozhou Chen  1 ,  Zhongren Wu  1 ,  Brian M McKeever  1 ,  Gerard M McGeehan  1 ,  Richard E Gregg  1 ,  David A Claremon  1 ,  Suresh B Singh  1
Affiliations
  • 1. Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
PMID: 26990539 DOI: 10.1021/acs.jmedchem.5b02029
Abstract

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.