Non-steroidal LXR agonists; an emerging therapeutic strategy for the treatment of atherosclerosis.
The Liver X Receptor (LXR) alpha and beta isoforms are members of the type II nuclear receptor family which function as obligate heterodimers with the Retinoid X Receptor (RXR). Upon agonist binding, the DNA Binding Domain (DBD) of LXR interacts with LXR response elements on target genes to initiate transcription. A number of genes have been shown to be modulated by LXR function, including the ATP-binding cassette transporter A1 (ABCA1). ABCA1 is involved in the process of reverse cholesterol transport (RCT) from macrophages in atherosclerotic plaques to high-density lipoproteins (HDL) in the plasma. Both homozygous and heterozygous mutations in ABCA1 result in conditions characterised by decreased levels of HDL and an earlier onset of atherosclerosis. A number of other genes are upregulated by LXR activation which would be expected to have either pro- or anti-atherogenic effects. One such target gene is sterol regulatory element binding protein-1c (SREBP-1c), which is involved in the process of lipogenesis leading to increased levels of triglycerides which are pro-atherogenic. The complexity of LXR responses, however, makes it difficult to extrapolate the 'positive' or 'negative' effects of each target gene in isolation to a conclusion as to the outcome in humans when all target genes are being modulated in concert. This review will cover the structural features and associated biological data of non-steroidal LXR modulators claimed for the treatment of cardiovascular disease, as well as highlighting preferred compounds where this information can be discerned. In addition to this patent information a précis of literature data relevant to the utility of specific compounds in the treatment of cardiovascular disease will be given where available.
Bennett
David J
DJ
Department of Chemistry, Organon Laboratories Ltd., Newhouse ML1 5SH, Scotland, UK. j.bennett@organon.co.uk
Cooke
Andrew J
AJ
Edwards
Andrew S
AS
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D004268:DNA-Binding Proteins / Q000819:agonists*; D064429:Fatty Acid Synthases / Q000235:genetics; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D053495:Osteopontin / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D013449:Sulfonamides / Q000627:therapeutic use; D013925:Thromboplastin / Q000235:genetics; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000103:Acetyl-CoA Carboxylase; D004268:DNA-Binding Proteins; D064429:Fatty Acid Synthases; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D053495:Osteopontin; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D013925:Thromboplastin; C577836:ABCA1 protein, human; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides