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 (EC50 = 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.

Department of Food Safety German Federal Institute for Risk Assessment Max Dohrn Str 8 10 10589 Berlin Germany

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy in Hradec Králové Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

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

School of Chemistry University of Lincoln Joseph Banks Laboratories Green Lane Lincoln Lincolnshire LN6 7DL United Kingdom

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