Leukotrienes: Regulation of Biosynthesis, Metabolism, and Bioactivity

Newcombe, CM David S.

doi:10.1002/j.1552-4604.1988.tb03173.x

Cited by 17 publications

(4 citation statements)

References 125 publications

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“…Products of the metabolism of arachidonic acid by the cyclooxygenase and, particularly, the lipoxygenase pathway are thought to be important mediators of acute inflammatory and anaphylatic responses (FordHutchinson, 1984;Newcombe, 1988;Hagmann, 1988). However, a lack of appropriate analytical methodology has confined assessment of their involvement in shock states, such as ischaemic or haemorrhagic shock, to the use of experimental leukotriene receptor antagonists and 5-lipoxygenase inhibitors in animal models (see Lefer 1986Lefer , 1989 for reviews).…”

Section: Introductionmentioning

confidence: 99%

Application of reversed phase high performance liquid chromatography to the analysis of sulphidopeptide leukotrienes in pig bile

Tagari¹,

Ethier²,

Ford‐Hutchinson³

et al. 1990

Biomedical Chromatography

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Reversed phase HPLC methodology has been developed for separation of peptide leukotrienes and indomethacin in porcine bile. Reproducible recoveries were obtained using radioactive leukotrienes ([3H]LTC4, 57.1 +/- 2.5%; [3H]LTE4, 62.7 +/- 1.9%; [3H]LTD4, 54.3 +/- 2.7%). Radioimmunoassay of column eluant demonstrated that as little as 300 pg of exogenous leukotrienes could be measured in bile fluids, with similar recoveries. Analysis of bile sampled 60-90 min after initiation of experimental endotoxic shock in indomethacin treated pigs revealed a leukotriene concentration of 5.24 +/- 1.16 ng/mL(LTD4). This was significantly greater (p less than 0.05, n = 3) than that observed in samples collected prior to endotoxin (0.42 +/- 0.23 ng/mL), or from untreated animals (0.85 +/- 0.51 ng/mL). This method is thus applicable to investigation of the role of 5-lipoxygenase products in porcine models of human disease, including shock conditions such as endotoxaemia, during cyclooxygenase inhibition by indomethacin.

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Section: Introductionmentioning

confidence: 99%

Application of reversed phase high performance liquid chromatography to the analysis of sulphidopeptide leukotrienes in pig bile

Tagari¹,

Ethier²,

Ford‐Hutchinson³

et al. 1990

Biomedical Chromatography

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“…Since the roles of arachidonic acid metabolites, such as leukotrienes (LTs), prostaglandins (PGs), and thromboxanes (TXs), as mediators of the inflammatory reaction were clarified, much effort has been made to develop inhibitors of the production of these chemical mediators as antiinflammatory agents. − These mediators also play important roles in some inflammatory or allergic diseases, acting either alone or in combination, , and inhibitors of 5-lipoxygenase (5-LO) and/or cyclooxygenase (CO) may be useful for the treatment of asthma, psoriasis, and rheumatoid arthritis, for example. − Dual inhibitors of CO and 5-LO have been under development, − but none has entered clinical use yet, and only nonsteroidal antiinflammatory drugs (NSAIDs) are used clinically. It should be noted that NSAIDs are not effective in some inflammatory diseases such as asthma and hepatitis, suggesting that inflammatory mediators other than PGs may play important roles in the pathology of these diseases.…”

Section: Introductionmentioning

confidence: 99%

Structure−Activity Relationships of (E)-3-(1,4-Benzoquinonyl)-2-[(3-pyridyl)- alkyl]-2-propenoic Acid Derivatives That Inhibit Both 5-Lipoxygenase and Thromboxane A₂ Synthetase

et al. 1996

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As part of our research for the development of novel antiinflammatory drug candidates, we have designed and synthesized a series of (E)-3-(1,4-benzoquinonyl)-2-[(3-pyridyl)alkyl]-2-propenoic acid derivatives as dual inhibitors of 5-lipoxygenase (5-LO) and thromboxane (TX) A2 synthetase. In order to increase the absorption after oral administration, we introduced a carboxylic acid moiety into the 1,4-benzoquinone skeleton, which has 5-LO-inhibitory character. Introduction of a 3-pyridylalkyl group at the double bond of the 1,4-benzoquinonyl propenoic acid moiety afforded good to moderate inhibitory activities against the production of leukotriene (LT) B4 and TXA2 while not significantly inhibiting that of prostaglandin E2 by glycogen-induced peritoneal cells of rat (in vitro). The length of the methylene chain of the 3-pyridylalkyl group influenced the inhibition of LTB4 and TXB2 production. An increase of lipophilicity by introducing a more lipophilic alkoxy group did not markedly increase the inhibitory activity on LTB4 production. The position of alkoxy group on the 1,4-benzoquinone skeleton played an important role in TXA2 synthetase inhibition. Compounds such as 20c (E6700) with an appropriate alkoxy group and proper length of methylene side chain, together with a polar substituent (carboxylic acid), showed good inhibition of both 5-LO and TXA2 synthetase and possess a variety of pharmacologically beneficial effects.

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“…Much effort has been directed at investigating the relationship between inflammatory diseases and arachidonic acid metabolites, such as the leukotrienes (LTs), prostaglandins (PGs), and thromboxanes (TXs). [1][2][3][4] During the past decade, it has become clear that these mediators play important roles in some inflammatory or allergic diseases, either acting alone or in combination.4•5 Extensive research has been undertaken to develop dual inhibitors of 5-lipoxygenase (5-LO) and cyclooxygenase (CO) with the expectation of superior effectiveness compared to individual enzyme inhibitors.6-9 However, at present there are no practicable dual inhibitors for the treatment of inflammatory diseases, and only nonsteroidal antiinflammatory drugs (NSAIDs) are used clinically. It also should be noted that new dual inhibitors affecting both 5-LO and thromboxane A2 (TXA2) synthetase are in development.…”

Section: Introductionmentioning

confidence: 99%

Novel Dual Inhibitors of 5-Lipoxygenase and Thromboxane A2 Synthetase: Synthesis and Structure-Activity Relationships of 3-Pyridylmethyl-Substituted 2-Amino-6-hydroxybenzothiazole Derivatives

Hibi¹,

Okamoto²,

Tagami³

et al. 1994

J. Med. Chem.

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As part of our search for novel antiinflammatory drug candidates, we have designed and synthesized a series of 3-pyridylmethyl-substituted 2-amino-6- hydroxybenzothiazoles. Introduction of a 3-pyridylmethyl group into the 2-amino group (type-A) or the benzene ring (type-B) of 2-amino-6-hydroxybenzothiazoles imparted dual inhibitory activity against the production by glycogen-induced peritoneal cells of rat (in vitro) of leukotriene B4 (LTB4) and thromboxane A2 (TXA2), while not significantly inhibiting that of prostaglandin E2 (PGE2). The observed inhibition of the former two arachidonic acid metabolites was indicated to be the result of a direct action on 5-lipoxygenase and TXA2 synthetase by a cell-free in vitro assay. On the other hand, the inhibitory activities against PGE2 production were for most compounds very weak, indicating that they did not inhibit cyclooxygenase. Structure-activity relationship studies concerning the position of the 3-pyridylmethyl group revealed that type-B compounds generally showed about 10-fold stronger inhibitory activity against TXA2 synthetase than type-A compounds. The position of the 3-pyridylmethyl group played an important role in TXA2 synthetase inhibition. When some of these compounds (8, 13a, 26a (E3040), 26b, 27b, and 28b) were orally administered in the rat TNB/ethanol-induced chronic colitis model (100 mg/kg), the production of both LTB4 and TXB2 in the rat colon was reduced (ex vivo). In addition, one type-B compound, 6-hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl)benzothiazole (26a), demonstrated a therapeutic effect at treatments of 100 mg/kg po once daily for 11 days and showed almost comparable activity to sulfasalazine at a dose of 500 mg/kg, the reference drug for inflammatory bowel diseases, in this in vivo model.

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Leukotrienes: Regulation of Biosynthesis, Metabolism, and Bioactivity

Cited by 17 publications

References 125 publications

Application of reversed phase high performance liquid chromatography to the analysis of sulphidopeptide leukotrienes in pig bile

Application of reversed phase high performance liquid chromatography to the analysis of sulphidopeptide leukotrienes in pig bile

Structure−Activity Relationships of (E)-3-(1,4-Benzoquinonyl)-2-[(3-pyridyl)- alkyl]-2-propenoic Acid Derivatives That Inhibit Both 5-Lipoxygenase and Thromboxane A₂ Synthetase

Novel Dual Inhibitors of 5-Lipoxygenase and Thromboxane A2 Synthetase: Synthesis and Structure-Activity Relationships of 3-Pyridylmethyl-Substituted 2-Amino-6-hydroxybenzothiazole Derivatives

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Leukotrienes: Regulation of Biosynthesis, Metabolism, and Bioactivity

Cited by 17 publications

References 125 publications

Application of reversed phase high performance liquid chromatography to the analysis of sulphidopeptide leukotrienes in pig bile

Application of reversed phase high performance liquid chromatography to the analysis of sulphidopeptide leukotrienes in pig bile

Structure−Activity Relationships of (E)-3-(1,4-Benzoquinonyl)-2-[(3-pyridyl)- alkyl]-2-propenoic Acid Derivatives That Inhibit Both 5-Lipoxygenase and Thromboxane A2 Synthetase

Novel Dual Inhibitors of 5-Lipoxygenase and Thromboxane A2 Synthetase: Synthesis and Structure-Activity Relationships of 3-Pyridylmethyl-Substituted 2-Amino-6-hydroxybenzothiazole Derivatives

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Structure−Activity Relationships of (E)-3-(1,4-Benzoquinonyl)-2-[(3-pyridyl)- alkyl]-2-propenoic Acid Derivatives That Inhibit Both 5-Lipoxygenase and Thromboxane A₂ Synthetase