Novel Thiazole Derivatives as Inhibitors of Superoxide Production by Human Neutrophils: Synthesis and Structure-Activity Relationships

Chihiro, Masatoshi; Nagamoto, Hisashi; Takemura, Isao; Kitano, Kazuyoshi; Komatsu, Hajime; Sekiguchi, Koichi; Tabusa, Fujio; Mori, Toyoki; Tominaga, Michiaki; Yabuuchi, Youichi

doi:10.1021/jm00002a017

Cited by 88 publications

(34 citation statements)

References 8 publications

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“…29,30) Tetomilast was originally discovered as a potent inhibitor of superoxide production in human neutrophils. 16) Although its mechanism of action is not completely understood, it is thought to have multiple molecular targets, including PDE4. The therapeutic effect of PDE4 inhibitors on COPD has been studied in cigarette smoke-exposure models, 31,32) but not in elastase instillation models.…”

Section: Discussionmentioning

confidence: 99%

“…Tetomilast exerts both vasoprotectant and anti-inflammatory effects, mediated by inhibition of PDE4 and superoxide production. 16) Tetomilast also attenuates acute lung injury, 17,18) and its anti-inflammatory effects have been noted in both the liver 19) and colon. 20) In the present study, we determine whether tetomilast could be an effective treatment for PPE-induced emphysema in rabbits.…”

Section: Tetomilast Attenuates Elastase-induced Pulmonary Emphysema Tmentioning

confidence: 98%

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Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

Baila

Ohno

Nagamoto

et al. 2012

Biological & Pharmaceutical Bulletin

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Tetomilast was originally identified as a potent inhibitor of superoxide production in human neutrophils, and is of interest because it may relieve oxidative stress related to chronic obstructive pulmonary disease (COPD). Our objective was to determine whether tetomilast effectively protects against the development of porcine pancreatic elastase (PPE)-induced emphysema in rabbits. Rabbits were divided into three groups (sham n 19, PPE n 19, PPE/Tetomilast n 18). The rabbits were once daily orally administered vehicle solution or tetomilast 5 d/week for 4 weeks before the PPE instillation. We compared pulmonary function, inflammatory cell infiltration, oxidative stress, and the incidences of apoptosis among the three groups. Tetomilast suppressed PPE-induced increases in the incidence of apoptosis and the production of 8-hydroxydeoxyguanosine (8-OHdG) in lung tissues. PPE-instilled rabbits treated with tetomilast showed significantly less mean linear intercept and significantly better pulmonary function than rabbits administered PPE alone. Tetomilast may inhibit the development of emphysema by attenuating pulmonary inflammation and apoptosis caused by PPE-induced oxidative stress.Key words chronic obstructive pulmonary disease; tetomilast; oxidative stress; 8-hydroxy-deoxyguanosine Pulmonary emphysema is a chronic, progressive obstructive pulmonary disease pathologically defined as "dilation of the alveolar space without desmoplasia by breakdown of alveolar walls and degradation of gas exchange." 1-6) Among the numerous factors known to play key roles in the pathogenesis of the disease are inflammation, reactive oxygen species (ROS), smoking, α 1 -antitrypsin defects and disequilibrium between elastase and anti-elastase, as well as between matrix metalloproteases (MMPs) and tissue MMP inhibitor.7-9) Airflow limitation in chronic obstructive pulmonary disease (COPD) patients results from mucosal inflammation and edema, bronchoconstriction, increased secretions in the airways and loss of elastic recoil. Phosphodiesterase 4 (PDE4) is expressed in almost all inflammatory cell types. While PDE4 inhibitors are very efficacious at inhibiting pro-inflammatory mediator release from certain cell types (e.g. neutrophils, eosinophils), 10,11) there is evidence to suggest that dual inhibition of PDE4 is additive or synergistic at suppressing the activation/ functions of other cell types, which are thought to play a role in COPD (e.g. macrophages, dendritic cells, epithelial cells, lymphocytes, airway smooth muscle cells and endothelial cells).12-15) Tetomilast (6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]-pyridine-2-carboxylic acid), a PDE4 inhibitor was initially isolated in vitro as the lead compound in a series of thiazole derivatives with inhibitory effects on superoxide production by human neutrophils. Tetomilast exerts both vasoprotectant and anti-inflammatory effects, mediated by inhibition of PDE4 and superoxide production.16) Tetomilast also attenuates acute lung injury, 17,18) and its anti-inflammatory effects have been n...

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Section: Discussionmentioning

confidence: 99%

Section: Tetomilast Attenuates Elastase-induced Pulmonary Emphysema Tmentioning

confidence: 98%

Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

Baila

Ohno

Nagamoto

et al. 2012

Biological & Pharmaceutical Bulletin

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“…Nitriles are of particular interest in preparative organic chemistry due to their rich chemistry [2][3][4][5][6]. They serve as useful precursors for the synthesis of amines, carboxylic acids, amides, ketones, and heterocyclic compounds, such as tetrazoles [7][8][9], thiazoles [10][11], oxazoles [12][13], 2-oxazolines [14] and 1,2-diarylimidazoles [15]. It has also been well documented that the cyano group itself is present in HIV protease inhibitors, 5-lipoxygenase inhibitors, and many other bioactive significant molecules [4,5].…”

Section: Introductionmentioning

confidence: 99%

Amberlite IR-120H: An improved reusable solid phase catalyst for the synthesis of nitriles under solvent free microwave irradiation

et al. 2012

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“…3-(Imidazol-2-yl)pyridines are known as inhibitors of xanthine oxidase, 11 nonsteroidal antiinflammatory agents, 12 potent and selective NPY5 receptor antagonists 13 as well as being tested as KDR kinase inhibitors. 14 3-(Thiazol-2-yl)pyridines are known as inhibitors of superoxide production by human neutrophils, 15 In view of above, it would be interesting to create a combinatorial library consisting of sterically hindered 3-(azolyl)pyridines 2-6 as derivatives of nicotinic acid ( Figure 1). Such combinatorial library would be also of interest since only two examples of 2,4,5-trisubstituted 3-(azolyl)pyridines [namely, 3-(1,2,4-oxadiazol-3-yl)pyridines, structure 4] were found in the literature.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of sterically hindered 3-(azolyl)pyridines

Lukyanov¹,

Bliznets²,

Shorshnev³

2008

Arkivoc

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Sterically hindered 2,4-disubstituted 3-(1,2,4-oxadiazol-3-yl)-, 3-(imidazol-2-yl)-and 3-(thiazol-2-yl)pyridines were synthesized from the corresponding nicotinonitriles via amidoximes, amidines and thioamides, respectively. N-Alkyl-and N-arylamidines were prepared directly from nicotinonitriles using microwave technology. The series of 3-(azolyl)pyridines form a combinatorial library of heterocyclic derivatives of nicotinic acid and were examined by prognostic software PASS.

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Novel Thiazole Derivatives as Inhibitors of Superoxide Production by Human Neutrophils: Synthesis and Structure-Activity Relationships

Cited by 88 publications

References 8 publications

Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

Tetomilast Attenuates Elastase-Induced Pulmonary Emphysema through Inhibition of Oxidative Stress in Rabbits

Amberlite IR-120H: An improved reusable solid phase catalyst for the synthesis of nitriles under solvent free microwave irradiation

Synthesis of sterically hindered 3-(azolyl)pyridines

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