Liver X receptor (LXR), a member of nuclear receptors superfamily, controls transcription of genes involved in regulation of cholesterol homeostasis, and its activation leads to increase of HDL-cholesterol and decrease of LDL-cholesterol levels.  However, activation of LXR also increases levels of triglycerides, since it controls genes involved in fatty acid synthesis.  This represents a serious obstacle in development of LXR ligands as drugs against atherosclerosis and cardiovascular disease.  To understand the effects shape, size and functionality of synthetic LXR ligands on the selective activation of either family of genes, we are synthesizing libraries of structurally-diverse ligands based on the trisubstituted alkene scaffold.  We have chosen haloallylic alcohols as such scaffolds, since they can be easily prepared from the common precursor, a propargylic alcohol, and then derivatized via orthogonal reactions to create a wide variety of ligands.  The synthesis of ligands and their biological properties will be presented.

Design and synthesis of trisubstituted alkene-based liver X receptor ligands as probes of LXR pharmacology

241st National Meeting (2011)

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