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 desirable pharmacokinetic profile and up regulation of ABCA1 and ABCG1 mRNA in the brain were achieved when evaluated in vivo in mice.
Swahn
Britt-Marie
BM
Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden. britt-marie.swahn@astrazeneca.com
Macsari
Istvan
I
Viklund
Jenny
J
Ohberg
Liselotte
L
Sjödin
Johanna
J
Neelissen
Jan
J
Lindquist
Johanna
J
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D007773:Lactates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000577:Amides; D004268:DNA-Binding Proteins; D007773:Lactates; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides