Further modification on phenyl acetic acid based quinolines as liver X receptor modulators.
A series of phenyl acetic acid based quinolines was prepared as LXR modulators. An SAR study in which the C-3 and C-8 positions of the quinoline core were varied led to the identification of two potent LXR agonists 23 and 27. Both compounds displayed good binding affinity for LXRbeta and LXRalpha, and increased expression of ABCA1 in THP-1 cells. These two compounds also had desirable pharmacokinetic profiles in mice and displayed in vivo efficacy in a 12-week Apo E knockout mouse lesion model.
Hu
Baihua
B
Chemical and Screening Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA. hub@wyeth.com
Jetter
James
J
Kaufman
David
D
Singhaus
Robert
R
Bernotas
Ronald
R
Unwalla
Rayomand
R
Quinet
Elaine
E
Savio
Dawn
D
Halpern
Anita
A
Basso
Michael
M
Keith
James
J
Clerin
Valerie
V
Chen
Liang
L
Liu
Qiang-Yuan
QY
Feingold
Irene
I
Huselton
Christine
C
Azam
Farooq
F
Goos-Nilsson
Annika
A
Wilhelmsson
Anna
A
Nambi
Ponnal
P
Wrobel
Jay
J
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016466:CHO Cells; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics; D006801:Humans; D007202:Indicators and Reagents; D000071518:Liver X Receptors; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012997:Solvents; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000235:genetics
D001057:Apolipoproteins E; D002264:Carboxylic Acids; D004268:DNA-Binding Proteins; D007202:Indicators and Reagents; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D012997:Solvents; C025136:phenylacetic acid