2-Substituted quinazolines: Partial agonistic and antagonistic ligands of the constitutive androstane receptor (CAR).

Autor: Brožová ZR; Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic., Dušek J; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic; Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03, Hradec Králové, Czech Republic., Palša N; Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic., Maixnerová J; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic., Kamaraj R; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic., Smutná L; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic., Matouš P; Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic., Braeuning A; Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany., Pávek P; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic., Kuneš J; Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic., Gathergood N; School of Chemistry, University of Lincoln, Joseph Banks Laboratories, Green Lane, Lincoln, Lincolnshire, LN6 7DL, United Kingdom., Špulák M; Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic., Pour M; Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic. Electronic address: pour@faf.cuni.cz., Carazo A; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic. Electronic address: carazofa@faf.cuni.cz.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 Nov 05; Vol. 259, pp. 115631. Date of Electronic Publication: 2023 Jul 13.
DOI: 10.1016/j.ejmech.2023.115631
Abstrakt: Following the discovery of 2-(3-methoxyphenyl)-3,4-dihydroquinazoline-4-one and 2-(3-methoxyphenyl)quinazoline-4-thione as potent, but non-specific activators of the human Constitutive Androstane Receptor (CAR, NR1I3), a series of quinazolinones substituted at the C2 phenyl ring was prepared to examine their ability to selectively modulate human CAR activity. Employing cellular and in vitro TR-FRET assays with wild-type CAR or its variant 3 (CAR3) ligand binding domains (LBD), several novel partial human CAR agonists and antagonists were identified. 2-(3-Methylphenyl) quinazolinone derivatives 7d and 8d acted as partial agonists with the recombinant CAR LBD, the former in nanomolar units (EC 50  = 0.055 μM and 10.6 μM, respectively). Moreover, 7d did not activate PXR, and did not show any signs of cytotoxicity. On the other hand, 2-(4-bromophenyl)quinazoline-4-thione 7l possessed significant CAR antagonistic activity, although the compound displayed no agonistic or inverse agonistic activities. A compound possessing purely antagonistic effect was thus identified for the first time. These and related compounds may serve as a remedy in xenobiotic intoxication or, conversely, in suppression of undesirable hepatic CAR activation.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Petr Pavek reports financial support was provided by Czech Science Foundation. Milan Pour reports financial support was provided by Charles University. Petr Pavek reports financial support was provided by Charles University. Petr Pavek reports financial support was provided by Ministry of Education Youth and Sports of the Czech Republic.
(Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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