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

共 140 条

[1] Pharmacological and clinical aspects of heme oxygenase [J].

Abraham, Nader G. ;

Kappas, Attallah .

PHARMACOLOGICAL REVIEWS, 2008, 60 (01) :79-127

[2] Bone marrow stem cell transplant into intra-bone cavity prevents type 2 diabetes: Role of heme oxygenase-adiponectin [J].

Abraham, Nader G. ;

Li, Ming ;

Vanella, Luca ;

Peterson, Stephen J. ;

Ikehara, Susumu ;

Asprinio, David .

JOURNAL OF AUTOIMMUNITY, 2008, 30 (03) :128-135

[3] Hypoxemia and blunted hypoxic ventilatory responses in mice lacking heme oxygenase-2 [J].

Adachi, T ;

Ishikawa, K ;

Hida, W ;

Matsumoto, H ;

Masuda, T ;

Date, F ;

Ogawa, K ;

Takeda, K ;

Furuyama, K ;

Zhang, YZ ;

Kitamuro, T ;

Ogawa, H ;

Maruyama, Y ;

Shibahara, S .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2004, 320 (02) :514-522

[4]

AFT RL, 1983, J BIOL CHEM, V258, P2069

[5]

AFT RL, 1984, J BIOL CHEM, V259, P301

[6] Update in Intracerebral Hemorrhage [J].

Aguilar, Maria I. ;

Brott, Thomas G. .

NEUROHOSPITALIST, 2011, 1 (03) :148-159

[7] Heme Oxygenase Database (HemeOxDB) and QSAR Analysis of Isoform1 Inhibitors [J].

Amata, Emanuele ;

Marrazzo, Agostino ;

Dichiara, Maria ;

Modica, Maria N. ;

Salerno, Loredana ;

Prezzavento, Orazio ;

Nastasi, Giovanni ;

Rescifina, Antonio ;

Romeo, Giuseppe ;

Pittala, Valeria .

CHEMMEDCHEM, 2017, 12 (22) :1873-1881

[8]

Amata E, 2017, DATA BRIEF, V15, P281, DOI 10.1016/j.dib.2017.09.036

[9]

[Anonymous], AM J PHYSL

[10] The mechanism(s) of hypoxic pulmonary vasoconstriction:: Potassium channels, redox O2 sensors, and controversies [J].

Archer, S ;

Michelakis, E .

NEWS IN PHYSIOLOGICAL SCIENCES, 2002, 17 :131-137

← 1 2 3 4 5 6 7 8 9 10 →