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Liver X receptor agonists with selectivity for LXRbeta; N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropionamides.

Swahn, Britt-Marie; Macsari, Istvan; Viklund, Jenny; Ohberg, Liselotte; Sjödin, Johanna; Neelissen, Jan; Lindquist, Johanna.

Bioorg Med Chem Lett ; 19(7): 2009-12, 2009 Apr 01.

Article in English | MEDLINE | ID: mdl-19264481

ABSTRACT

The synthesis and SAR of a new series of LXR agonist is reported. The N-Aryl-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide hits were found in a limited screen of the AstraZeneca compound collection. The effort to optimize these hits into LXRbeta selectivity is described. Compound 20 displayed desirable pharmacokinetic profile and up regulation of ABCA1 and ABCG1 mRNA in the brain were achieved when evaluated in vivo in mice.

Subject(s)

Amides/pharmacology , DNA-Binding Proteins/agonists , Lactates/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Sulfonamides/pharmacology , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/metabolism , Amides/chemical synthesis , Amides/chemistry , Animals , Brain/metabolism , Cell Line , Computer Simulation , DNA-Binding Proteins/metabolism , Genes, Reporter , Humans , Lactates/chemical synthesis , Lactates/chemistry , Liver X Receptors , Mice , Orphan Nuclear Receptors , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Up-Regulation

ABSTRACT

Subject(s)

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