Discovery and structure-activity relationship studies of indole derivatives as liver X receptor (LXR) agonists.
A structurally novel liver X receptor (LXR) agonist (1) was identified from internal compound collection utilizing the combination of structure-based virtual screening and high-throughput gene profiling. Compound 1 increased ABCA1 gene expression by eightfold and SREBP1c by threefold in differentiated THP-1 macrophage cell lines. Confirmation of its agonistic activity against LXR was obtained in the co-factor recruitment and reporter transactivation assays. Structure-activity relationship studies on compound 1 are described.
Bakir
Farid
F
Department of Chemistry, Tanabe Research Laboratories USA, Inc., 4540 Towne Centre Court, San Diego, CA 92121, USA.
Kher
Sunil
S
Pannala
Madhavi
M
Wilson
Norma
N
Nguyen
Trang
T
Sircar
Ila
I
Takedomi
Kei
K
Fukushima
Chiaki
C
Zapf
James
J
Xu
Kui
K
Zhang
Shao-Hui
SH
Liu
Juping
J
Morera
Lisa
L
Schneider
Lisa
L
Sakurai
Naoki
N
Jack
Rick
R
Cheng
Jie-Fei
JF
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008956:Models, Chemical; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; 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
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; 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