New potent antagonists of leukotrienes C4 and D4. 1. Synthesis and structure-activity relationships

Nakai, Hisao; Konno, Mitoshi; Kosuge, Shunji; Sakuyama, Shigeru; Toda, Masaaki; Arai, Yoshinobu; Obata, Takaaki; Katsube, Nobuo; Miyamoto, Tsumoru

doi:10.1021/jm00396a013

Cited by 88 publications

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“…Leukotriene D 4 (LTD 4 ), one of the cysteinyl leukotrienes (CysLT), induces contraction of the tracheal muscle and has potent effects on leukocyte trafficking, airway mucus secretion and collagen synthesis in bronchial asthma [1,2,3]. Normal peripheral blood leukocytes, such as basophils, eosinophils, B lymphocytes and monocytes/macrophages, have a CysLT1 receptor [4].…”

Section: Introductionmentioning

confidence: 99%

Cysteinyl Leukotrienes Induce Monocyte Chemoattractant Protein-1 in Human Monocyte/Macrophages via Mitogen-Activated Protein Kinase and Nuclear Factor-κB Pathways

Hashimoto

Ichiyama

Hasegawa

et al. 2009

Int Arch Allergy Immunol

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Background: We have previously demonstrated that cysteinyl leukotriene (CysLT) induced monocyte chemoattractant protein-1 (MCP-1) production in monocytes/macrophages. The intracellular signal transduction pathway of MCP-1 production induced by CysLT in human monocytes/macrophages is unclear. Methods: The activation of mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK by phosphorylation, and nuclear factor-κB (NF-κB) by leukotriene (LT) D₄ and LTC₄ was determined in THP-1 cells, a human monocytic leukemia cell line, and peripheral blood CD14+ monocytes/macrophages. We examined the inhibitory effects of inhibitors of ERK1/2, JNK, p38 MAPK and NF-κB and pranlukast as a CysLT1 receptor antagonist on induction of MCP-1 production by LTD₄ and LTC₄. Results: LTD₄ and LTC₄ induced significant phosphorylations of ERK1/2 and JNK, but not p38 MAPK, in THP-1 cells and peripheral blood CD14+ monocytes/macrophages. Pretreatment with the ERK1/2 inhibitor PD98059 and JNK inhibitor SP600125 attenuated MCP-1 production by CysLTs. NF-κB activation was induced by addition of LTD₄ and LTC₄. Pretreatment with the NF-κB inhibitors caffeic acid phenylethyl ester and MG-132 inhibited MCP-1 production by CysLTs. Pranlukast inhibited phosphorylation of ERK1/2 and JNK, NF-κB activation, and the MCP-1 production induced by CysLTs. Conclusion: CysLTs induce MCP-1 and this induction is mediated by ERK1/2 and JNK in MAPK, and NF-κB pathways via the CysLT1 receptor, for the most part, in human monocytes/macrophages.

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Section: Introductionmentioning

confidence: 99%

Cysteinyl Leukotrienes Induce Monocyte Chemoattractant Protein-1 in Human Monocyte/Macrophages via Mitogen-Activated Protein Kinase and Nuclear Factor-κB Pathways

Hashimoto

Ichiyama

Hasegawa

et al. 2009

Int Arch Allergy Immunol

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“…However, the therapeutic potential of this com pound was limited by its poor oral bioavailability and its short biological half life (14,15). Our recent efforts have focused on the design of high-affinity and orally active peptide LT antagonists from the derivatives of (p-amylcinnamoyl) anthranilic acid (16). This resulted in the discovery of 4-oxo-8-[4 (4-phenylbutoxy) benzoylamino]-2-(tetrazol-5-yl)-4H-1 benzopyran hemihydrate (ONO-1078) ( Fig.…”

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confidence: 99%

In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.

et al. 1992

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ABSTRACT-We investigated the in vivo antagonistic activity of ONO-1078 against peptide leuko trienes (LTs) in guinea pigs. ONO-1078, when administered p.o. (0.3-3 mg/kg), caused a dose-depend ent reduction of LTC4-, LTD4 and LTE4-induced bronchoconstriction, LTD4-induced airway micro vascular leakage and LTD4-induced increase in cutaneous vascular permeability. When administered in travenously, ONO-1078 (3 30 ,u g/kg) inhibited these responses approximately 200 600 fold more potently than FPL55712. When guinea pigs were treated with indomethacin to examine the antagonism of ONO-1078 on the direct action against peptide LTs, intravenous (3 30 ,u g/kg) and oral (0.3-3 mg/kg) administration of ONO-1078 also inhibited LTC4 and LTD4-induced bronchoconstriction, and its activity was approximately 300 500 fold more potent than that of FPL55712. ONO-1078 (10 mg/kg, i.v.) had no inhibitory effect on bronchoconstrictions induced by histamine, acetylcholine, serotonin, arachidonic acid, LTB4, prostaglandin (PG) F2a , PGD2, 9a ,11,Q-PGF2, a stable thromboxane A2 mi metic agent and platelet activating factor. Furthermore, oral administration of ONO-1078 (1-10 mg/kg) inhibited slow-reacting substance of anaphylaxis mediated bronchoconstriction induced by antigen in a dose-dependent manner. These results indicate that ONO-1078 is an extremely potent, selective and orally active peptide LT antagonist and that oral administration of ONO-1078 antagonizes not only ex ogenously administered peptide LTs but also endogenous peptide LTs.

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“…[19][20][21][22][23] The Cys-LT1 receptor antagonists montelukast and pranlukast are well known to have clinical benefits for the treatment and management of allergic diseases, particularly asthma. Several studies have suggested that pranlukast inhibits lipopolysaccharide-induced IL-6, allergen-specific tumor necrosis factor-a (TNFa) and T helper-2 (T h 2)-type cytokine production and the translocation of NF-kB, a ubiquitous transcription factor for genes that encode pro-inflammatory cytokines such as IL-1, IL-6, IL-8, and TNFa.…”

Section: Il-4 and Il-5)mentioning

confidence: 99%

Effects of Leukotriene Receptor Antagonists on Peripheral Eosinophil Counts and Serum IgE Levels in Children with Food Allergy

et al. 2010

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Background: Although the efficacy of leukotriene receptor antagonists (LTRAs) for bronchial asthma is already established, their effect on food allergy remains unclear. Objective: To investigate the efficacy of LTRAs in children with food allergy. Methods: This retrospective study examined 65 children with food allergy who were aged between 3 and 36 months (mean 14 -9.6 months) from 2005 to 2008. Thirty-two children were treated as a dietary control group by avoiding any antigenic foods to which they had previously experienced adverse reactions. The remaining 33 children, designated the LTRA group, were treated with pranlukast (7 mg/kg bodyweight/day) in addition to maintaining dietary control. Clinical symptoms and laboratory data before and after 1 year of treatment were compared between the groups. Results: Allergic symptoms improved in both the dietary controlled and LTRA groups, and there was no significant difference observed in the clinical parameters examined between the groups after the 1-year trial. Peripheral eosinophil count, serum IgE, interleukin (IL)-4, IL-5, IL-6, and eosinophil cationic protein (ECP) levels in children with food allergy were above standardized values in both groups. Although both the dietary controlled and LTRA groups showed a decreased eosinophil count (-273 -232 vs -595 -295/mL; p < 0.05 and p < 0.001, respectively), only children treated with LTRA showed a significant decrease in serum IgE (-73.5 -115 IU/mL; p < 0.01); conversely, the control group exhibited a significant increase in serum IgE (+159 -138 IU/mL; p < 0.01). Furthermore, the LTRA group also showed a significant decrease in serum IL-4 (54.5 -31.0 to 27.3 -10.1 pg/mL), IL-5 (6.7 -5.2 to 5.0 -0.4 pg/mL), and ECP (45.4 -15.0 to 15.0 -9.8 mg/L) levels (p < 0.05 for each).

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New potent antagonists of leukotrienes C4 and D4. 1. Synthesis and structure-activity relationships

Cited by 88 publications

References 0 publications

Cysteinyl Leukotrienes Induce Monocyte Chemoattractant Protein-1 in Human Monocyte/Macrophages via Mitogen-Activated Protein Kinase and Nuclear Factor-κB Pathways

Cysteinyl Leukotrienes Induce Monocyte Chemoattractant Protein-1 in Human Monocyte/Macrophages via Mitogen-Activated Protein Kinase and Nuclear Factor-κB Pathways

In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.

Effects of Leukotriene Receptor Antagonists on Peripheral Eosinophil Counts and Serum IgE Levels in Children with Food Allergy

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