Synthesis and evaluation of anilinohexafluoroisopropanols as activators/modulators of LXRα and β

A series of branched and unbranched anilinohexafluoroisopropanols related to the known sulfonamide T0901317 were prepared and evaluated as activators/modulators of both LXRα and LXRβ. 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 LXRβ versus LXRα. 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.

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