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Discovery of Novel Human Constitutive Androstane Receptor Agonists with the Imidazo[1,2-a]pyridine Structure
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SYSNO ASEP 0579804 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Discovery of Novel Human Constitutive Androstane Receptor Agonists with the Imidazo[1,2-a]pyridine Structure Author(s) Mejdrova, I. (CZ)
Dušek, J. (CZ)
Škach, K. (CZ)
Štefela, A. (CZ)
Škoda, J. (CZ)
Chalupský, Karel (UMG-J)
Dohnalová, Klára (UMG-J)
Pávková, I. (CZ)
Kronenberger, T. (DE)
Rashidian, A. (DE)
Smutná, L. (CZ)
Duchoslav, V. (CZ)
Smutný, T. (CZ)
Pávek, P. (CZ)
Nencka, R. (CZ)Number of authors 15 Source Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 66, č. 4 (2023), s. 2422-2456Number of pages 35 s. Language eng - English Country US - United States Keywords pregnane-x-receptor ; car ; activation ; pxr ; ligand ; derivatives ; identification ; artemisinin ; metabolites ; expression OECD category Cell biology R&D Projects LM2015040 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA22-05167S GA ČR - Czech Science Foundation (CSF) ED2.1.00/19.0395 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 001162433000001 EID SCOPUS 85147860531 DOI 10.1021/acs.jmedchem.2c01140 Annotation 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2024 Electronic address https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01140
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