The nuclear constitutive androstane receptor (CAR, NR1I3) plays significant roles in many hepatic functions, such as fatty acid oxidation, biotransformation, liver regeneration, as well as clearance of steroid hormones, cholesterol, and bilirubin. CAR has been proposed as a hypothetical target receptor for metabolic or liver disease therapy. Currently known prototype high-affinity human CAR agonists such as CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) have limited selectivity, activating the pregnane X receptor (PXR) receptor, a related receptor of the NR1I subfamily. We have discovered several derivatives of 3-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine that directly activate human CAR in nanomolar concentrations. While compound 39 regulates CAR target genes in humanized CAR mice as well as human hepatocytes, it does not activate other nuclear receptors and is nontoxic in cellular and genotoxic assays as well as in rodent toxicity studies. Our findings concerning potent human CAR agonists with in vivo activity reinforce the role of CAR as a possible therapeutic target.

1st Medical Faculty Charles University Katerinska 32 112 08 Prague Czech Republic

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Vídeňská 1083 142 20 Prague Czech Republic

Department of Internal Medicine 8 University Hospital of Tübingen 72076 Tübingen Germany

Department of Pharmaceutical and Medicinal Chemistry Institute of Pharmaceutical Sciences Eberhard Karls Universität 72076 Tübingen Germany

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University Akademika Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Faculty of Military Health Sciences University of Defense Trebeska 1575 500 01 Hradec Kralove Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nám 2 166 10 Prague 6 Czech Republic

School of Pharmacy Faculty of Health Sciences University of Eastern Finland 70211 Kuopio Finland

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