Liver X Receptors (LXRs) a and � are ligand activated transcription factors of the nuclear receptor superfamily involved in cholesterol metabolism, lipogenesis and glucose homeostasis. LXRa is the dominant subtype in the liver, while LXR� is distributed ubiquitously.            Elevation of triglyceride (TG) in plasma and liver in animal models is an adverse effect reported for many other LXR agonists, and is thought to be caused by up-regulation of SREBP1-C following LXRa activation in liver.Therefore in our attempt to differentiate between these two LXR subtypes and            discovering LXR� selective agonists for the treatment of atherosclerosis,                              we have synthesized an LXR� agonist, K-20770-2b, with high potency and selectivity        (EC50 for LXRa:250 nM, EC50 for LXR�: 3.5 nM, a/� ratio: 71).In a 10-week multiple oral dose study in low-density lipoprotein receptor knockout mice,         K-20770-2b enhanced blood ABCA1 mRNA expression and suppressed lipid accumulation        in aortic valve areas by 20% at a dose of 0.1 mg/kg/day without elevation of plasma TG.       In contrast, the non-selective compound GW3965 (10 mg/kg) also prevented aortic lipiddeposition, but markedly increased plasma TG. K-20770-2b enhances the reversecholesterol transport system without affecting TG levels and provides a novelapproach for the treatment of atherosclerosis.The synthesis, structure-activity relationships and pharmacological effects of K-20770-2b arepresented.

Discovery of a highly potent and selective Liver X Receptor � agonist, K-20770-2b

248th National Meeting (2014)

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