Pyrimidinylimidazole inhibitors of p38: cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity

Adams, Jerry L.; Boehm, Jeffrey C.; Gallagher, Timothy F.; Kassis, Shouki; Webb, Edward F.; Hall, Ralph F.; Sorenson, Margaret E.; Garigipati, Ravi S.; Griswold, Don E.; Lee, John C.

doi:10.1016/s0960-894x(01)00570-4

Cited by 107 publications

(54 citation statements)

References 14 publications

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“…Previous reports have established that inhibition of ERK1/ERK2, p38, or JNK alone is sufficient to inhibit cytokine production. [31][32][33] For example blocking p38 inhibits production of TNF in monocytes. Our data suggest that the combined effects of the inhibition of p38, ERK, and JNK is likely to be responsible for the profound inhibitory effect of 4-HNE on the production of TNF in human macrophages.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Lipopolysaccharide-Induced Stimulation of the Members of the MAPK Family in Human Monocytes/Macrophages by 4-Hydroxynonenal, a Product of Oxidized Omega-6 Fatty Acids

Marantos

Mukaro

Ferrante

et al. 2008

The American Journal of Pathology

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The compound 4-hydroxynonenal (4-HNE) is the major aldehyde formed during lipid peroxidation of -6-polyunsaturated fatty acids and has been suggested to regulate inflammatory responses because it inhibits tumor necrosis factor (TNF) mRNA production in the human monocytic cell line THP-1. Here we demonstrate that 4-HNE inhibits TNF and interleukin-1␤ production in human monocytes in response to lipopolysaccharide. The main action of 4-HNE occurred at the pretranscriptional level; there was no effect on TNF mRNA production or stability when 4-HNE was added after stimulation. The mechanism of action of 4-HNE appears to be downstream of lipopolysaccharide-receptor binding. In the human monocytic MonoMac 6 cell line, 4-HNE caused selective inhibition of the activity of the mitogen-activated protein kinases p38 and ERK1/ERK2, but not JNK. However, in monocytes, the activities of all three kinases were inhibited, suggesting that the effects of 4-HNE were exerted at points upstream of ERK1/ERK2 and JNK as the levels of the phosphorylated kinases were reduced. In contrast, p38 phosphorylation was not inhibited, suggesting that 4-HNE affects kinase activity. 4-HNE also inhibited nuclear factor-B activation in monocytes. In view of the roles of p38, ERK1/ERK2, JNK, and nuclear factor-B in inflammation, the data suggest that 4-HNE, at nontoxic concentrations, has antiinflammatory properties, most likely through an effect on these signaling molecules, and could lead to the development of novel treatments for inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Lipopolysaccharide-Induced Stimulation of the Members of the MAPK Family in Human Monocytes/Macrophages by 4-Hydroxynonenal, a Product of Oxidized Omega-6 Fatty Acids

Marantos

Mukaro

Ferrante

et al. 2008

The American Journal of Pathology

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“…Imidazole drugs have broadened scope in remedying various dispositions in clinical medicines. Medicinal properties include anticancer [11], b-lactamase inhibitors [12], 20-HETE synthase inhibitors [13], carboxypeptidase inhibitors [14], hemeoxygenase inhibitors [15], antiaging agents [16], anticoagulants [17], anti-inflammatory [18], antibacterial [19], antifungal [20], antiviral [21], antitubercular [22], antidiabetic [23] and antimalarial [24], all are unique characteristics known for imidazole derivatives.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antimicrobial and antiviral evaluation of substituted imidazole derivatives

Sharma

Narasimhan

Kumar

et al. 2009

European Journal of Medicinal Chemistry

207

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“…Compounds containing imidazole and benzothiazole moiety have shown a wide range of biological properties including anticancer, antiviral, antitubercular, antimicrobial, antidiabetic, anti-inflammatory activities. These broad thera-peutic properties of imidazole and benzothiazole related drugs have encouraged the medicinal chemists in order to synthesize novel chemotherapeutic agents [3][4][5][6][7][8][9][10][11][12][13][14][15][16] . Dr. Malcolm Stevens, a researcher of Cancer Research UK Group at Nottingham University demonstrated the potential of benzothiazole (NSC 674495) and related compounds as anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

Novel benzothiazole based imidazole derivatives as new cytotoxic agents against glioma (C6) and liver (hepG2) cancer cell lines

Yurttaş¹,

Ertaş²,

Çiftçi³

et al. 2017

actapharm

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Pyrimidinylimidazole inhibitors of p38: cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity

Cited by 107 publications

References 14 publications

Inhibition of the Lipopolysaccharide-Induced Stimulation of the Members of the MAPK Family in Human Monocytes/Macrophages by 4-Hydroxynonenal, a Product of Oxidized Omega-6 Fatty Acids

Inhibition of the Lipopolysaccharide-Induced Stimulation of the Members of the MAPK Family in Human Monocytes/Macrophages by 4-Hydroxynonenal, a Product of Oxidized Omega-6 Fatty Acids

Synthesis, antimicrobial and antiviral evaluation of substituted imidazole derivatives

Novel benzothiazole based imidazole derivatives as new cytotoxic agents against glioma (C6) and liver (hepG2) cancer cell lines

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