title: Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) β Agonist.
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.
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Linghang
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Kristi Yi
authors.initials: KY
authors.lastname: Fan
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Colin M
authors.initials: CM
authors.lastname: Tice
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Chengguo
authors.initials: C
authors.lastname: Dong
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Lotesta
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Katerina
authors.initials: K
authors.lastname: Leftheris
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Lindblom
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Shimada
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Noto
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Shi
authors.initials: S
authors.lastname: Meng
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hardy
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Lamont
authors.initials: L
authors.lastname: Howard
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Paula
authors.initials: P
authors.lastname: Krosky
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Joan
authors.initials: J
authors.lastname: Guo
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Kerri
authors.initials: K
authors.lastname: Lipinski
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Geeta
authors.initials: G
authors.lastname: Kandpal
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bukhtiyarov
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Deepak
authors.initials: D
authors.lastname: Lala
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Van Orden
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Guozhou
authors.initials: G
authors.lastname: Chen
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Zhongren
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: McKeever
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Gerard M
authors.initials: GM
authors.lastname: McGeehan
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gregg
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Claremon
authors.affiliation: Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D001596:Benzylamines / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D010879:Piperazines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C000611065:(2-(4-(4-(hydroxymethyl)-3-(methylsulfonyl)phenyl)-2-isopropylpiperazin-1-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol; D001596:Benzylamines; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D010879:Piperazines; D011743:Pyrimidines; D013450:Sulfones