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

被引：6

作者：

Brozova, Zuzana Rania ^{[1
]}

Dusek, Jan ^{[2
,3
]}

Palsa, Norbert ^{[1
]}

Maixnerova, Jana ^{[2
]}

Kamaraj, Rajamanikkam ^{[2
]}

Smutna, Lucie ^{[2
]}

Matous, Petr ^{[1
]}

Braeuning, Albert ^{[4
]}

Pavek, Petr ^{[2
]}

Kunes, Jiri ^{[1
]}

Gathergood, Nicholas ^{[5
]}

Spulak, Marcel ^{[1
]}

Pour, Milan ^{[1
]}

Carazo, Alejandro ^{[2
]}

机构：

[1] Charles Univ Prague, Fac Pharm Hradec Kralove, Dept Organ & Bioorgan Chem, Heyrovskeho 1203, Hradec Kralove 50005, Czech Republic

[2] Charles Univ Prague, Fac Pharm Hradec Kralove, Dept Pharmacol & Toxicol, Heyrovskeho 1203, Hradec Kralove 50005, Czech Republic

[3] Charles Univ Prague, Fac Med Hradec Kralove, Dept Physiol, Simkova 870, Hradec Kralove 50003, Czech Republic

[4] German Fed Inst Risk Assessment, Dept Food Safety, Max Dohrn Str 8-10, D-10589 Berlin, Germany

[5] Univ Lincoln, Sch Chem, Joseph Banks Labs, Green Lane, Lincoln LN6 7DL, Lincs, England

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 259卷

关键词：

CAR; Gene activation; Quinazolines; Xenobiotics; Nuclear receptors; Metabolism; ACTIVATION; HETERODIMER; DERIVATIVES; GROWTH; AMIDES; PXR;

D O I：

10.1016/j.ejmech.2023.115631

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页数：17

共 61 条

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