Synthesis, Crystal Structure, and Activity of Pyrazole-Based Inhibitors of p38 Kinase

Graneto, Matthew J.; Kurumbail, Ravi G.; Vazquez, Michael L.; Shieh, Huey‐Sheng; Pawlitz, Jennifer L.; Williams, Jennifer M.; Stallings, William C.; Geng, Lifeng; Naraian, Ashok S.; Koszyk, Francis J.; Stealey, Michael A.; Xu, Xiangdong; Weier, Richard M.; Hanson, Gunnar J.; Mourey, Robert J.; Compton, Robert P.; Mnich, Stephen J.; Anderson, Gary D.; Monahan, Joseph B.; Devraj, Rajesh

doi:10.1021/jm0611915

Cited by 64 publications

(24 citation statements)

References 30 publications

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“…6C). This level of inhibition was similar to studies using anti-TNF-␣ antibody therapy using a similar protocol (Graneto et al, 2007). Lower doses, 4 and 12 mg/kg/ day, were less effective in affecting incidence.…”

supporting

confidence: 80%

Anti-Inflammatory Properties of a NovelN-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation

Hope¹,

Anderson²,

Burnette³

et al. 2009

J Pharmacol Exp Ther

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Signal transduction through the p38 mitogen-activated protein (MAP) kinase pathway is central to the transcriptional and translational control of cytokine and inflammatory mediator production. p38 MAP kinase inhibition hence constitutes a promising therapeutic strategy for treatment of chronic inflammatory diseases, based upon its potential to inhibit key pathways driving the inflammatory and destructive processes in these debilitating diseases. The present study describes the pharmacological properties of the Nphenyl pyridinone p38 MAP kinase inhibitor benzamide [3-[3-bromo-4-[(2,4-PH-797804 is an ATP-competitive, readily reversible inhibitor of the ␣ isoform of human p38 MAP kinase, exhibiting a K i ϭ 5.8 nM. In human monocyte and synovial fibroblast cell systems, PH-797804 blocks inflammation-induced production of cytokines and proinflammatory mediators, such as prostaglandin E 2 , at concentrations that parallel inhibition of cell-associated p38 MAP kinase. After oral dosing, PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. Furthermore, PH-797804 demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Finally, PH-797804 reduced tumor necrosis factor-␣ and interleukin-6 production in clinical studies after endotoxin administration in a dose-dependent manner, paralleling inhibition of the target enzyme. Low-nanomolar biochemical enzyme inhibition potency correlated with p38 MAP kinase inhibition in human cells and in vivo studies. In addition, a direct correspondence between p38 MAP kinase inhibition and antiinflammatory activity was observed with PH-797804, thus providing confidence in dose projections for further human studies in chronic inflammatory disease.Rheumatoid arthritis (RA) is an aggressive autoimmune disease involving complex interactions among T cells, macrophages, synoviocytes, and other immune cells (Firestein, 2003). Analysis of synovial fluid and tissue from RA patients implicated key cytokines, including TNF-␣, IL-1␤, and IL-6 in the pathogenesis of the disease (Firestein et al., 1990). Further studies shed light on the complex networks within which these cytokines function and the delicate balance between a pro-or an anti-inflammatory outcome (McInnes and ABBREVIATIONS: RA, rheumatoid arthritis; TNF, tumor necrosis factor; IL, interleukin; COX, cyclooxygenase; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH 2 -terminal kinase; benzamide,methoxy]-6-methyl-2-oxo-1(2H)-pyridinyl]-N,4-dimethyl-, (Ϫ)-(9CI); SCW, streptococcal cell wall; LPS, lipopolysaccharide; MKK, mitogen-activated protein kinase kinase; EGFRP, epidermal growth factor receptor peptide; GST, glutathione transferase; RASF, rheumatoid arthritis synovial fibroblast(s); MK-2, mitogen-activated protein kinase-act...

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supporting

confidence: 80%

Anti-Inflammatory Properties of a NovelN-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation

Hope¹,

Anderson²,

Burnette³

et al. 2009

J Pharmacol Exp Ther

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“…PHA-408 (H.-C. Huang, unpublished data describing the synthesis procedure) and p38 MAPK inhibitor SC-806 (Graneto et al, 2007) were synthesized at Pfizer Inc. For in vitro assays, inhibitors were dissolved in Me 2 SO and stored at Ϫ20°C in 50 mM aliquots.…”

Section: Methodsmentioning

confidence: 99%

“…5A). The magnitude of PHA-408 inhibition of TNF-␣ production was similar to that of the benchmark inhibitor, dexamethasone, and the potent and selective p38 MAPK inhibitor, SC-806 (Graneto et al, 2007). Liver lysates from LPS and/or PHA-408-treated rats were generated to assess IB␣ and other MAPK pathways by Western analysis.…”

Section: Pha-408 Selectively Inhibits Il-1␤-and Lps-induced Expressiomentioning

confidence: 98%

A Novel, Highly Selective, Tight Binding IκB Kinase-2 (IKK-2) Inhibitor: A Tool to Correlate IKK-2 Activity to the Fate and Functions of the Components of the Nuclear Factor-κB Pathway in Arthritis-Relevant Cells and Animal Models

Mbalaviele¹,

Sommers

Bonar

et al. 2009

J Pharmacol Exp Ther

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Nuclear factor (NF)-B activation has been clearly linked to the pathogenesis of multiple inflammatory diseases including arthritis. The central role that IB kinase-2 (IKK-2) plays in regulating NF-B signaling in response to inflammatory stimuli has made this enzyme an attractive target for therapeutic intervention. Although diverse chemical classes of IKK-2 inhibitors have been identified, the binding kinetics of these inhibitors has limited the scope of their applications. In addition, safety assessments of IKK-2 inhibitors based on a comprehensive understanding of the pharmacokinetic/pharmacodynamic relationships have yet to be reported. Here, we describe a novel, potent, andPHA-408 is an ATPcompetitive inhibitor, which binds IKK-2 tightly with a relatively slow off rate. In arthritis-relevant cells and animal models, PHA-408 suppresses inflammation-induced cellular events, including IB␣ phosphorylation and degradation, p65 phosphorylation and DNA binding activity, the expression of inflammatory mediators, and joint pathology. PHA-408 was efficacious in a chronic model of arthritis with no adverse effects at maximally efficacious doses. Stemming from its ability to bind tightly to IKK-2, as a novelty, we demonstrated that PHA-408-mediated inhibition of IKK-2 activity correlated very well with its ability to modulate the fate of IKK-2 substrates and downstream transcriptional events. We ultimately directly linked IKK-2 activity ex vivo and in vivo to markers of inflammation with the inhibitor plasma concentrations. Thus, PHA-408 represents a powerful tool to further gain insight into the mechanisms by which IKK-2 regulates NF-B signaling and validates IKK-2 as a therapeutic target.The NF-B family of inducible transcription factors regulates the expression of numerous genes, which are central to developmental and immune processes, cell survival, proliferation, and differentiation (Baeuerle and Henkel, 1994). However, dysregulated NF-B activity leads to the onset of several human pathologies, including cancer and inflammatory diseases such as rheumatoid arthritis, asthma, and in-G.M. and C.D.S. contributed equally to this work. Article, publication date, and citation information can be found at

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“…In medicine, derivatives of pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antianhythmic, tranquilizing, muscle relaxing, psychoanaleptic, and anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities [2][3][4]. Some of them are active ingredients of products with potential antitumor activity [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Molecular structure, vibrational spectral studies of pyrazole and 3,5-dimethyl pyrazole based on density functional calculations

Krishnakumar

Jayamani²,

Mathammal³

2011

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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Synthesis, Crystal Structure, and Activity of Pyrazole-Based Inhibitors of p38 Kinase

Cited by 64 publications

References 30 publications

Anti-Inflammatory Properties of a NovelN-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation

Anti-Inflammatory Properties of a NovelN-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation

A Novel, Highly Selective, Tight Binding IκB Kinase-2 (IKK-2) Inhibitor: A Tool to Correlate IKK-2 Activity to the Fate and Functions of the Components of the Nuclear Factor-κB Pathway in Arthritis-Relevant Cells and Animal Models

Molecular structure, vibrational spectral studies of pyrazole and 3,5-dimethyl pyrazole based on density functional calculations

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