Abstract
1 Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell-mediated inflammation of the bronchial mucosa. 2 Recruitment and activation of inflammatory cells is orchestrated by a variety of mediators such as cytokines, chemokines, or adhesion molecules, the expression of which is regulated via the transcription factor nuclear factor kappa B (NF-kappaB). 3 NF-kappaB signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a critical catalytic subunit of which is IKK-beta. 4 We identified COMPOUND A as a small-molecule, ATP-competitive inhibitor selectively targeting IKK-beta kinase activity with a K(i) value of 2 nM. 5 COMPOUND A inhibited stress-induced NF-kappaB transactivation, chemokine-, cytokine-, and adhesion molecule expression, and T- and B-cell proliferation. 6 COMPOUND A is orally bioavailable and inhibited the release of LPS-induced TNF-alpha in rodents. 7 In mice COMPOUND A inhibited cockroach allergen-induced airway inflammation and hyperreactivity and efficiently abrogated leukocyte trafficking induced by carrageenan in mice or by ovalbumin in a rat model of airway inflammation. 8 COMPOUND A was well tolerated by rodents over 3 weeks without affecting weight gain. 9 Furthermore, in mice COMPOUND A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed-type hypersensitivity. 10 These data suggest that IKK-beta inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / adverse effects
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Cell Adhesion Molecules / antagonists & inhibitors
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Cell Adhesion Molecules / biosynthesis
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Edema / prevention & control
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Female
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Humans
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I-kappa B Kinase
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I-kappa B Proteins / metabolism
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Leukocytes / cytology
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Leukocytes / drug effects
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Leukocytes / physiology
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Male
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Mice
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Mice, Inbred BALB C
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Oxazines / adverse effects
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Oxazines / pharmacokinetics
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Oxazines / pharmacology*
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Phosphorylation
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Pneumonia / immunology
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Pneumonia / prevention & control*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyridines / adverse effects
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Rats
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Rats, Wistar
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Signal Transduction / drug effects
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Transcriptional Activation / drug effects
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / metabolism
Substances
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7-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido(2,3-d)(1,3)oxazin-2-one
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Anti-Inflammatory Agents, Non-Steroidal
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Cell Adhesion Molecules
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I-kappa B Proteins
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NF-kappa B
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NFKBIA protein, human
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Nfkbia protein, mouse
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Nfkbia protein, rat
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Oxazines
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Pyridines
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse