Heme Oxygenase-2 (HO-2) as a therapeutic target: Activators and inhibitors

被引：50

作者：

Intagliata, Sebastiano ^{[1
]}

Salerno, Loredana ^{[1
]}

Ciaffaglione, Valeria ^{[1
]}

Leonardi, Carmen ^{[1
]}

Fallica, Antonino N. ^{[1
]}

Carota, Giuseppe ^{[1
]}

Amata, Emanuele ^{[1
]}

Marrazzo, Agostino ^{[1
]}

Pittala, Valeria ^{[1
]}

Romeo, Giuseppe ^{[1
]}

机构：

[1] Univ Catania, Dept Drug Sci, Viale A Doria 6, I-95125 Catania, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 183卷

关键词：

Heme oxygenase-2; Heme oxygenase-1; Imidazole derivatives; Activators; Azalanstat; Clemizole; Structure-activity relationships; EXPERIMENTAL INTRACEREBRAL HEMORRHAGE; IMIDAZOLE-DIOXOLANE COMPOUNDS; EARLY REPRESSOR ICER; IN-VITRO INHIBITION; CARBON-MONOXIDE; REGULATORY MOTIFS; OXIDATIVE STRESS; SELECTIVE-INHIBITION; BILIVERDIN REDUCTASE; HYDROGEN-SULFIDE;

D O I：

10.1016/j.ejmech.2019.111703

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Heme oxygenase (HO) enzymes are involved in heme catabolism and several physiological functions. Among the different HO isoforms, HO-2 stands out for its neuroprotective properties and modulatory activity in male reproduction. However, unlike the HO-1 ligands, the potential therapeutic applications of HO-2 inhibitors/activators have not been extensively explored yet. Moreover, the physiological role of HO-2 is still unclear, mostly due to the lack of highly selective HO-2 chemical probes. To boost the interest on this intriguing target, the present review updates the knowledge on the structure-activity relationships of HO-2 inhibitors and activators, as well as their potential therapeutic applications. To the best of our knowledge, among HO-2 inhibitors, clemizole derivatives are the most selective HO-2 inhibitors reported so far (IC50 HO-1 >100 mu M, IC50 HO-2 = 3.4 mu M), while the HO-2 nonselective inhibitors described herein possess IC50 HO-2 values < 10 mu M. Furthermore, the development of HO-2 activators, such as menadione analogues, helped to understand the critical moieties required for HO-2 activation. Recent advances in the potential therapeutic applications of HO-2 inhibitors/activators cover the fields of neurodegenerative, cardiovascular, inflammatory, and reproductive diseases further stimulating the interest towards this target. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页数：16

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