Synthesis and evaluation of anilinohexafluoroisopropanols as activators/modulators of LXRalpha and beta.
A series of branched and unbranched anilinohexafluoroisopropanols related to the known sulfonamide T0901317 were prepared and evaluated as activators/modulators of both LXRalpha and LXRbeta. A structure-activity relationship was established and compounds with high potency on both the receptors were identified. Many compounds showed a tendency toward selectivity for LXRbeta versus LXRalpha. Several analogues were evaluated for effects on plasma lipoprotein levels in mice. A few of these significantly raised HDL-cholesterol levels in plasma but showed markedly different effects on liver triglyceride content, suggesting that this series may yield candidates with improved efficacy/safety profiles compared to existing molecules.
Panday
Narendra
N
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Preclinical Research, CH-4070 Basel, Switzerland. npanday@epo.org
Benz
Jörg
J
Blum-Kaelin
Denise
D
Bourgeaux
Vanessa
V
Dehmlow
Henrietta
H
Hartman
Peter
P
Kuhn
Bernd
B
Ratni
Hassen
H
Warot
Xavier
X
Wright
Matthew B
MB
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy; D008076:Cholesterol, HDL / Q000097:blood; D004268:DNA-Binding Proteins / Q000187:drug effects*; D008074:Lipoproteins / Q000097:blood; D008099:Liver; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D020005:Propanols / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
D000814:Aniline Compounds; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D008074:Lipoproteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D020005:Propanols; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides