Synthesis of liver X receptor agonists from hydeoxycholic acid

Liver X receptor(LXRs) are members of nuclear receptor superfamily,responsible for the regulation of cholesterol metabolism.Dysfunction in cholesterol metabolism may result in cardio-and cerebral-vascular diseases,such as ischemic stroke,coronary artery atherosclerosis and Alzheimer′s disease.Hyodeoxycholic acid,an abundant by-product from livestock industry,is used as steroidal scaffold to synthesize LXR modulators.Three bile acid analogs were synthesized and evaluated in an in vitro biological assay using the human embryonic kidney cell line HEK293 and a commercial dual-luciferase reporter gene method.4-((3R,5R,6S,10R,13R)-3,6-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N,N-dimethylpentanamide(1) and 4-((3R,5R,6S,10R,13R)-3,6-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-methyl-N-(3,4,5-trimethoxybenzyl)pentanamide(2) showed agonist activity toward both LXRα and LXRβ,while 2-((3R,5R,6S,10R,13S)-3,6-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-(3,4,5-trimethoxybenzyl)propanamide(3)de-monstrated LXR sub-type selectivity and only activated LXRα.Further analysis is needed to develop these bile acid analogs and their derivatives into clinically useful LXR regulators.