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Treatment of allergic asthma by targeting janus kinase 3-dependent leukotriene synthesis in mast cells with 4-(3', 5'-dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97).

Abstract
4-(3',5'-Dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97) is a rationally designed potent inhibitor of Janus kinase (JAK)-3. Treatment of mast cells with WHI-P97 inhibited the translocation of 5-lipoxygenase (5-LO) from the nucleoplasm to the nuclear membrane and consequently 5-LO-dependent leukotriene (LT) synthesis after IgE receptor/FcepsilonRI crosslinking by >90% at low micromolar concentrations. WHI-P97 did not directly inhibit the enzymatic activity of 5-LO, but prevented its translocation to the nuclear membrane without affecting the requisite calcium signal. WHI-P97 was very well tolerated in mice, with no signs of toxicity at dose levels ranging from 5 microg/kg to 50 mg/kg, and LD(10) was not reached at a 50 mg/kg dose level when administered as a single i. p. or i.v. bolus dose. Therapeutic WHI-P97 concentrations, which inhibit mast cell leukotriene synthesis in vitro, could easily be achieved in vivo after the i.v. or i.p. administration of a single nontoxic 40 mg/kg bolus dose of WHI-P97. Notably, WHI-P97 showed promising biological activity in a mouse model of allergic asthma at nontoxic dose levels. Treatment of ovalbumin-sensitized mice with WHI-P97 prevented the development of airway hyper-responsiveness to methacholine in a dose-dependent fashion. Furthermore, WHI-P97 inhibited the eosinophil recruitment to the airway lumen after the ovalbumin challenge in a dose-dependent fashion. Further development of WHI-P97 may therefore provide the basis for new and effective treatment as well as prevention programs for allergic asthma in clinical settings.
AuthorsR Malaviya, C L Chen, C Navara, R Malaviya, X P Liu, M Keenan, B Waurzyniak, F M Uckun
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 295 Issue 3 Pg. 912-26 (Dec 2000) ISSN: 0022-3565 [Print] United States
PMID11082424 (Publication Type: Journal Article)
Chemical References
  • Anti-Asthmatic Agents
  • Enzyme Inhibitors
  • Quinazolines
  • Receptors, IgE
  • WHI P97
  • Arachidonic Acid
  • Leukotriene C4
  • Calcimycin
  • Arachidonate 5-Lipoxygenase
  • Protein-Tyrosine Kinases
  • Jak3 protein, mouse
  • Janus Kinase 3
Topics
  • Animals
  • Anti-Asthmatic Agents (pharmacokinetics, pharmacology)
  • Arachidonate 5-Lipoxygenase (metabolism)
  • Arachidonic Acid (metabolism)
  • Calcimycin (pharmacology)
  • Enzyme Inhibitors (pharmacology)
  • Eosinophils (drug effects, physiology)
  • Female
  • Janus Kinase 3
  • Leukotriene C4 (biosynthesis)
  • Male
  • Mast Cells (drug effects, metabolism)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, SCID
  • Protein-Tyrosine Kinases (antagonists & inhibitors, physiology)
  • Quinazolines (pharmacokinetics, pharmacology)
  • Receptors, IgE (physiology)

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