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

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 desi...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-04, Vol.19 (7), p.2009-2012
Hauptverfasser:	Swahn, Britt-Marie, Macsari, Istvan, Viklund, Jenny, Ohberg, Liselotte, Sjödin, Johanna, Neelissen, Jan, Lindquist, Johanna
Format:	Artikel
Sprache:	eng
Schlagworte:	Amides - chemical synthesis Amides - chemistry Amides - pharmacology Animals ATP Binding Cassette Transporter 1 ATP-Binding Cassette Transporters - metabolism Brain - metabolism Cell Line Computer Simulation DNA-Binding Proteins - agonists DNA-Binding Proteins - metabolism Genes, Reporter Humans Lactates - chemical synthesis Lactates - chemistry Lactates - pharmacology Liver X Receptors Mice Orphan Nuclear Receptors Receptors, Cytoplasmic and Nuclear - agonists Receptors, Cytoplasmic and Nuclear - metabolism Structure-Activity Relationship Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacology Up-Regulation
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Zusammenfassung:	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.
ISSN:	1464-3405
DOI:	10.1016/j.bmcl.2009.02.039