1-(3-Aryloxyaryl)benzimidazole sulfones are liver X receptor agonists.
A series of 1-(3-aryloxyaryl)benzimidazoles incorporating a sulfone substituent (6) was prepared. High affinity LXR ligands were identified (LXRbeta binding IC(50) values <10nM), some with excellent agonist potency and efficacy in a functional assay of LXR activity measuring ABCA1 mRNA increases in human macrophage THP1 cells. The compounds were typically stable in liver microsome preparations and had good oral exposure in mice.
Travins
Jeremy M
JM
Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA.
Bernotas
Ronald C
RC
Kaufman
David H
DH
Quinet
Elaine
E
Nambi
Ponnal
P
Feingold
Irene
I
Huselton
Christine
C
Wilhelmsson
Anna
A
Goos-Nilsson
Annika
A
Wrobel
Jay
J
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002460:Cell Line; D006801:Humans; D000071518:Liver X Receptors; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry*
D018528:ATP-Binding Cassette Transporters; D001562:Benzimidazoles; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D013450:Sulfones