Synthesis of 4-(3-biaryl)quinoline sulfones as potent liver X receptor agonists.
A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.
Ullrich
John W
JW
Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA. JWUllrich@comcast.net
Morris
Robert
R
Bernotas
Ronald C
RC
Travins
Jeremy M
JM
Jetter
James
J
Unwalla
Rayomand
R
Quinet
Elaine
E
Nambi
Ponnal
P
Feingold
Irene
I
Huselton
Christine
C
Enroth
Christofer
C
Wilhelmsson
Anna
A
Goos-Nilsson
Annika
A
Wrobel
Jay
J
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D006801:Humans; D008077:Lipoproteins, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D011804:Quinolines; D013450:Sulfones; C037219:quinoline