A selective novel low-molecular-weight inhibitor of IkappaB kinase-beta (IKK-beta) prevents pulmonary inflammation and shows broad anti-inflammatory activity.

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.

• Authors: Karl Ziegelbauer, Florian Gantner, Nicholas W Lukacs, Aaron Berlin, Kinji Fuchikami, Toshiro Niki, Katsuya Sakai, Hisayo Inbe, Keisuke Takeshita, Mina Ishimori, Hiroshi Komura, Toshiki Murata, Timothy Lowinger, Kevin B Bacon
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 145 Issue 2 Pg. 178-92 (May 2005) ISSN: 0007-1188 [Print] England
• PMID: 15753951 (Publication Type: Journal Article)

Chemical References

• 7-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido(2,3-d)(1,3)oxazin-2-one
• Anti-Inflammatory Agents, Non-Steroidal
• Cell Adhesion Molecules
• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• Nfkbia protein, mouse
• Nfkbia protein, rat
• Oxazines
• Pyridines
• Tumor Necrosis Factor-alpha
• NF-KappaB Inhibitor alpha
• Protein Serine-Threonine Kinases
• CHUK protein, human
• Chuk protein, mouse
• I-kappa B Kinase
• IKBKB protein, human
• IKBKE protein, human
• Ikbkb protein, mouse
• Ikbke protein, mouse

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (adverse effects, pharmacokinetics, pharmacology)
• Cell Adhesion Molecules (antagonists & inhibitors, biosynthesis)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Edema (prevention & control)
• Female
• Humans
• I-kappa B Kinase
• I-kappa B Proteins (metabolism)
• Leukocytes (cytology, drug effects, physiology)
• Male
• Mice
• Mice, Inbred BALB C
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors, metabolism)
• Oxazines (adverse effects, pharmacokinetics, pharmacology)
• Phosphorylation
• Pneumonia (immunology, prevention & control)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pyridines (adverse effects, pharmacokinetics, pharmacology)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)
• Transcriptional Activation (drug effects)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, biosynthesis, metabolism)