Bicyclic Imidazoles as a Novel Class of Cytokine Biosynthesis Inhibitors

Lee, J. C.; Badger, Alison M.; Griswold, Don E.; Dunnington, Damien J.; Truneh, Alemseged; Votta, Bartholomew J.; White, John R.; Young, Peter R.; Bender, Paul E.

doi:10.1111/j.1749-6632.1993.tb17149.x

Cited by 141 publications

(41 citation statements)

References 57 publications

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“…Also, up-regulation of IL-1b and TNF-a gene expression is mediated by p38 MAP kinase in various models, and p38 MAP kinase inhibitors suppress the gene expression and production of these cytokines [11,14,15,16,17,18,19]. Therefore, it is possible that the inhibition of p38 MAP kinase activation prevents the development of HUS-like lesions in this model.…”

Section: Introductionmentioning

confidence: 96%

“…It is well known that IL-1b and TNF-a are potent activators of the p38 MAP kinase cascade, and there has been accumulating evidence that multiple responses to these cytokines are mediated by p38 MAP kinase [10,11,12,13]. Also, up-regulation of IL-1b and TNF-a gene expression is mediated by p38 MAP kinase in various models, and p38 MAP kinase inhibitors suppress the gene expression and production of these cytokines [11,14,15,16,17,18,19].…”

Section: Introductionmentioning

confidence: 99%

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Role of p38 MAP kinase pathway in a toxin-induced model of hemolytic uremic syndrome

Iijima

Nozu

et al. 2004

Pediatr Nephrol

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The role of proinflammatory cytokines in a rat model of toxin-induced hemolytic uremic syndrome (HUS) was studied. Male Sprague-Dawley rats underwent continuous saline infusion (6 ml/h) via a tail vein and received a bolus injection of saline (control), lipopolysaccharide (LPS, 10 microg/100 g body weight), ricin (6.7 microg/100 g body weight), or ricin with LPS (ricin+LPS). They were then observed for 8 h. Blood samples and kidney tissues were obtained at the end of the experiment. The effects of FR 167653, a potent inhibitor of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) production, were also examined in ricin+LPS-treated rats. Only ricin+LPS-treated rats developed significant thrombocytopenia, hemolysis, and oliguric acute renal failure with extensive glomerular thrombotic microangiopathy, which was characterized by glomerular microthrombi and apoptosis of glomerular endothelial cells. Thrombotic microangiopathy was not detected in other organs, including the brain, liver, spleen, pancreas, lung, colon, and intestine. Significantly elevated levels of serum IL-1beta and TNF-alpha were detected only in ricin+LPS-treated rats. Treatment of ricin+LPS-treated rats with FR 167653 significantly reduced the serum levels of IL-1beta and TNF-alpha, accompanied by improvement of the oliguric renal failure and glomerular thrombotic microangiopathy. These findings indicate that the increased serum levels of IL-1beta and TNF-alpha, which probably result in the apoptosis of glomerular endothelial cells, play a pivotal role in the development of this rat model of toxin-induced HUS. The findings also suggest that inhibition of these proinflammatory cytokines may prevent the development of HUS.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Role of p38 MAP kinase pathway in a toxin-induced model of hemolytic uremic syndrome

Iijima

Nozu

et al. 2004

Pediatr Nephrol

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“…Inhibition of p38␣ (and its homolog, p38␤) by inhibitors such as SB203580 and BIRB 796, reduces LPS-induced production of proinflammatory cytokines, including TNF␣ and IL-1, that are implicated in the etiology of chronic inflammation (1)(2)(3)(4)(5). Recent genetic evidence suggests that p38␣, not p38␤, is the major p38 isoform involved in the LPS-induced immune response (6).…”

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confidence: 99%

Molecular basis of MAPK-activated protein kinase 2:p38 assembly

White

Pargellis

Studts

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

106

109

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p38 MAPK and MAPK-activated protein kinase 2 (MK2) are key components of signaling pathways leading to many cellular responses, notably the proinflammatory cytokine production. The physical association of p38␣ isoform and MK2 is believed to be physiologically important for this signaling. We report the 2.7-Å resolution crystal structure of the unphosphorylated complex between p38␣ and MK2. These protein kinases bind ''head-to-head,'' present their respective active sites on approximately the same side of the heterodimer, and form extensive intermolecular interactions. Among these interactions, the MK2 Ile-366 -Ala-390, which includes the bipartite nuclear localization signal, binds to the p38␣-docking region. This binding supports the involvement of noncatalytic regions to the tight binding of the MK2:p38␣ binary assembly. The MK2 residues 345-365, containing the nuclear export signal, block access to the p38␣ active site. Some regulatory phosphorylation regions of both protein kinases engage in multiple interactions with one another in this complex. This structure gives new insights into the regulation of the protein kinases p38␣ and MK2, aids in the better understanding of their known cellular and biochemical studies, and provides a basis for understanding other regulatory protein-protein interactions involving signal transduction proteins.X-ray structure T he MAPK has been directly associated with proinflammatory cytokine production. Inhibition of p38␣ (and its homolog, p38␤) by inhibitors such as SB203580 and BIRB 796, reduces LPS-induced production of proinflammatory cytokines, including TNF␣ and IL-1, that are implicated in the etiology of chronic inflammation (1-5). Recent genetic evidence suggests that p38␣, not p38␤, is the major p38 isoform involved in the LPS-induced immune response (6). Embryonic stem cells derived from mice that lack the p38␣ function exhibit impaired IL-1 signaling (7). Biological therapies directed against inflammatory cytokines, e.g., anti-TNF␣ and anti-IL-1␤, have also proven effective at ameliorating the symptoms of inflammatory diseases such as arthritis and psoriasis (not anti-IL-1␤-mediated) (8-11).MAPK-activated protein kinase-2 (MK2), the primary substrate of p38␣, is also a key participant in modulating proinflammatory cytokine production (12, 13). MK2 knockout mice (MK2 Ϫ/Ϫ ) challenged with LPS produce significantly less TNF␣, IL-6, IFN␥, and IL-1 than LPS-stimulated wild-type mice (13). MK2Ϫ/Ϫ mice are also resistant to collagen-induced arthritis (14). The transfection of cultured keratinocytes with MK2-specific small interfering RNA led to a significant decrease in MK2 protein expression and a subsequent, significant reduction in the production of TNF␣, . The catalytic activity of MK2 has further been shown to be necessary for TNF␣ production (16). Taken together, these data suggest that the inhibition of the p38␣ pathway, particularly MK2, is desirable for the potential treatment of chronic inflammation.In resting cells, p38␣ forms a physiological complex with MK2, w...

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“…These studies explored dual 5-lipoxygenase/cyclooxygenase (LO/COX) and cytokine inhibition as a potential mechanism for the activity of these compounds. [19] Subsequently, SB-203580 and other 2,4,5-triaryl imidazoles were prepared as pharmacological tools to be used in the search for the molecular target involved in cytokine regulation. [20] Pyridinylimidazoles containing pyridin-4-yl and 4-fluorophenyl groups were the first representative inhibitors shown to bind to the ATP-binding pocket of p38 MAP kinase.…”

Section: Introductionmentioning

confidence: 99%

Substituted Isoxazoles as Potent Inhibitors of p38 MAP Kinase

2006

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In a continuous effort to develop improved p38 MAP (mitogen-activated protein) kinase inhibitors, we focused our attention on the suitability of the isoxazole ring as a bioisosteric replacement for the imidazole ring of SB-203580. 3,4- and 4,5-disubstituted as well as 3,4,5-trisubstituted isoxazole derivatives were synthesized. These compounds were tested in an in vitro enzyme-linked immunosorbent assay of isolated p38 MAP kinase and for inhibitory potency against cytochrome P450. Compound 4 a displays a highly promising profile for development as an anti-inflammatory agent owing to its enhanced suppression of cytokine release, decreased affinity for cytochrome P450 and a twofold decrease in IC50 toward isolated p38 MAP kinase.

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Bicyclic Imidazoles as a Novel Class of Cytokine Biosynthesis Inhibitors

Cited by 141 publications

References 57 publications

Role of p38 MAP kinase pathway in a toxin-induced model of hemolytic uremic syndrome

Role of p38 MAP kinase pathway in a toxin-induced model of hemolytic uremic syndrome

Molecular basis of MAPK-activated protein kinase 2:p38 assembly

Substituted Isoxazoles as Potent Inhibitors of p38 MAP Kinase

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