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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F23%3A10471252" target="_blank" >RIV/00216208:11150/23:10471252 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11160/23:10471252

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=LJJgX-SOai" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=LJJgX-SOai</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2023.115631" target="_blank" >10.1016/j.ejmech.2023.115631</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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 mu M and 10.6 mu M, 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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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 mu M and 10.6 mu M, 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

1768-3254

Svazek periodika

259

Číslo periodika v rámci svazku

November

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

17

Strana od-do

115631

Kód UT WoS článku

001045022900001

EID výsledku v databázi Scopus

2-s2.0-85166004436