Quinoline-3-carboxamide containing sulfones as liver X receptor (LXR) agonists with binding selectivity for LXRbeta and low blood-brain penetration.
A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRbeta and moderate binding selectivity over LXRalpha. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRbeta over LXRalpha (LXRbeta IC(50)=16nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRalpha Gal4 functional assay, and low blood-brain barrier penetration in rat.
Hu
Baihua
B
Chemical Science, Collegeville, PA, USA. hub@wyeth.com
Bernotas
Ron
R
Unwalla
Rayomand
R
Collini
Michael
M
Quinet
Elaine
E
Feingold
Irene
I
Goos-Nilsson
Annika
A
Wilhelmsson
Anna
A
Nambi
Ponnal
P
Evans
Mark
M
Wrobel
Jay
J
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002460:Cell Line; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D011804:Quinolines; D013450:Sulfones