Carboxylic acid based quinolines as liver X receptor modulators that have LXRbeta receptor binding selectivity.
A series of potent and binding selective LXRbeta agonists was developed using the previously reported non-selective LXR ligand WAY-254011 as a structural template. With the aid of molecular modeling, it was found that 2,3-diMe-Ph, 2,5-diMe-Ph, and naphthalene substituted quinoline acetic acids (such as quinoline 33, 37, and 38) showed selectivity for LXRbeta over LXRalpha in binding assays.
Hu
Baihua
B
Chemical and Screening Sciences, Wyeth Pharmaceuticals, Collegeville, PA 19426, USA. hub@wyeth.com
Quinet
Elaine
E
Unwalla
Rayomand
R
Collini
Mike
M
Jetter
James
J
Dooley
Rebecca
R
Andraka
Diane
D
Nogle
Lisa
L
Savio
Dawn
D
Halpern
Anita
A
Goos-Nilsson
Annika
A
Wilhelmsson
Anna
A
Nambi
Ponnal
P
Wrobel
Jay
J
D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D057093:Orphan Nuclear Receptors; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D015533:Transcriptional Activation
D002264:Carboxylic Acids; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear