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/FcεRI 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 μg/kg to 50 mg/kg, and LD10was 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.
Footnotes
-
Send reprint requests to: Dr. Fatih M. Uckun, Parker Hughes Institute, 2665 Long Lake Rd., Suite 300, St. Paul, MN 55113. E-mail:fatih_uckun{at}mercury.ih.org
- Abbreviations:
- LT
- leukotriene
- WHI-P97
- 4-(3′,5′-dibromo-4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline
- WHI-P131
- 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline
- WHI-P112
- 4-(2′,5′-dibromophenyl)amino-6,7-dimethoxyquinazoline
- 5-LO
- 5-lipoxygenase
- FLAP
- 5-LO-activating protein, 5-HPETE, 5-hydroperoxyeicosatetraenoic acid
- 5-HETE
- 5-hydroxyeicosatetraenoic acid
- TX
- thromboxane
- PG
- prostaglandin
- PMSF
- phenylmethylsulfonyl fluoride
- JAK3
- Janus kinase 3
- DNP
- dinitrophenyl
- BMMC
- bone marrow mast cells
- TEA
- triethylamine
- ELISA
- enzyme-linked immunosorbent assay
- OVA
- ovalbumin
- Penh
- enhanced pause
- COX
- cyclooxygenase
- PIPES
- 1,4-piperazinediethanesulfonic acid
- Received July 12, 2000.
- Accepted August 11, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|