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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 0569356 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) Mejdrová, Ivana (UOCHB-X)
Dušek, J. (CZ)
Škach, Kryštof (UOCHB-X)
Štefela, A. (CZ)
Škoda, J. (CZ)
Chalupský, Karel (UOCHB-X)
Dohnalová, K. (CZ)
Pavková, I. (CZ)
Kronenberger, T. (DE)
Rashidian, A. (DE)
Smutná, L. (CZ)
Duchoslav, Vojtěch (UOCHB-X)
Smutný, T. (CZ)
Pávek, P. (CZ)
Nencka, Radim (UOCHB-X) RID, ORCIDSource 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 OECD category Pharmacology and pharmacy R&D Projects TN01000013 GA TA ČR - Technology Agency of the Czech Republic (TA ČR) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000929753300001 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 Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2024 Electronic address https://doi.org/10.1021/acs.jmedchem.2c01140
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