Synthesis and SAR of potent LXR agonists containing an indole pharmacophore.
A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXRalpha will be disclosed.
Washburn
David G
DG
Department of Chemistry, Molecular Discovery Research, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA. dave.g.washburn@gsk.com
Hoang
Tram H
TH
Campobasso
Nino
N
Smallwood
Angela
A
Parks
Derek J
DJ
Webb
Christine L
CL
Frank
Kelly A
KA
Nord
Melanie
M
Duraiswami
Chaya
C
Evans
Christopher
C
Jaye
Michael
M
Thompson
Scott K
SK
D000284:Administration, Oral; D000818:Animals; D002784:Cholesterol / Q000032:analysis; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000819:agonists*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013329:Structure-Activity Relationship
D004268:DNA-Binding Proteins; D007211:Indoles; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol