1-(3-Aryloxyaryl)benzimidazole sulfones are liver X receptor agonists

Jeremy M Travins; Ronald C Bernotas; David H Kaufman; Elaine Quinet; Ponnal Nambi; Irene Feingold; Christine Huselton; Anna Wilhelmsson; Annika Goos-Nilsson; Jay Wrobel

doi:10.1016/j.bmcl.2009.11.099

1-(3-Aryloxyaryl)benzimidazole sulfones are liver X receptor agonists

Bioorg Med Chem Lett. 2010 Jan 15;20(2):526-30. doi: 10.1016/j.bmcl.2009.11.099. Epub 2009 Nov 23.

Authors

Jeremy M Travins¹, Ronald C Bernotas, David H Kaufman, Elaine Quinet, Ponnal Nambi, Irene Feingold, Christine Huselton, Anna Wilhelmsson, Annika Goos-Nilsson, Jay Wrobel

Affiliation

¹ Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA.

PMID: 20006495
DOI: 10.1016/j.bmcl.2009.11.099

Abstract

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.

MeSH terms

ATP-Binding Cassette Transporters / genetics
ATP-Binding Cassette Transporters / metabolism
Animals
Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry
Benzimidazoles / pharmacokinetics
Cell Line
Humans
Liver X Receptors
Mice
Microsomes, Liver / metabolism
Orphan Nuclear Receptors / agonists*
Orphan Nuclear Receptors / metabolism
RNA, Messenger / metabolism
Rats
Structure-Activity Relationship
Sulfones / chemistry*

Substances

ATP-Binding Cassette Transporters
Benzimidazoles
Liver X Receptors
Orphan Nuclear Receptors
RNA, Messenger
Sulfones