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

Br J Pharmacol. 2005 May;145(2):178-92. doi: 10.1038/sj.bjp.0706176.

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

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cell Adhesion Molecules / antagonists & inhibitors
  • Cell Adhesion Molecules / 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
  • Leukocytes / drug effects
  • Leukocytes / physiology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Oxazines / adverse effects
  • Oxazines / pharmacokinetics
  • Oxazines / pharmacology*
  • Phosphorylation
  • Pneumonia / immunology
  • Pneumonia / prevention & control*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Transcriptional Activation / drug effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 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