title: 2-Aryl-N-acyl indole derivatives as liver X receptor (LXR) agonists.
abstract: Structure-activity relationship studies on a series of Boc-indole derivatives as LXR agonists are described. Compound 1 was identified as an LXR agonist through structure-based virtual screening followed by high-throughput gene profiling. Replacement of the indan linker portion in 1 with an open-chain linker resulted in compounds with similar or improved in vitro potency and cellular functional activity. The Boc group at the N-1 position of the indole moiety can be replaced with a benzoyl group. The SAR studies led to the identification of compound 8, a potent LXRbeta agonist with an EC50 of 12 nM in the cofactor recruitment assay.
authors.affiliation: Department of Chemistry, Tanabe Research Laboratories USA, Inc., 4540 Towne Centre Court, San Diego, CA 92121, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kher
authors.forename: Kirk
authors.initials: K
authors.lastname: Lake
authors.forename: Ila
authors.initials: I
authors.lastname: Sircar
authors.forename: Madhavi
authors.initials: M
authors.lastname: Pannala
authors.forename: Farid
authors.initials: F
authors.lastname: Bakir
authors.forename: James
authors.initials: J
authors.lastname: Zapf
authors.forename: Kui
authors.initials: K
authors.lastname: Xu
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: Zhang
authors.forename: Juping
authors.initials: J
authors.lastname: Liu
authors.forename: Lisa
authors.initials: L
authors.lastname: Morera
authors.forename: Naoki
authors.initials: N
authors.lastname: Sakurai
authors.forename: Rick
authors.initials: R
authors.lastname: Jack
authors.forename: Jie-Fei
authors.initials: JF
authors.lastname: Cheng
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D000071518:Liver X Receptors; D008958:Models, Molecular; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D007211:Indoles; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1