Identification of 4-[4-(4-Fluoro-Phenyl)-Thiazol-2-Ylamino]-2,6-Dimethyl-Phenol (KR-33749) as an Inhibitor of 5-Lipoxygenase with Potent Antiinflammatory Activity.

Background/Aim: To discover new 5-lipoxygenase (5-LO) inhibitors applicable to inflammation-related skin disease, we identified and examined antiinflammatory properties of a novel 5-LO inhibitor, KR-33749, in vitro and in vivo. Methods: 5-LO enzyme activity was assayed using insect cell lysates overexpressing rat 5-LO. The leukotriene B4 (LTB4) level was assayed in rat basophilic leukemia (RBL-1) cell line. Mouse ear edema was induced by topical application of arachidonic acid. Atopic dermatitis-like skin lesion was induced by topical application of 1-chloro-2,4-dinitrobenzene (DNCB) to NC/Nga mice. Results: KR-33749 inhibited 5-LO activity with an IC50 value of 70.5 ± 6.0 nmol/l in parallel with LTB4 inhibition in RBL-1 cells. The compound exhibited a >1,000-fold selectivity against 12-LO and 15-LO. KR-33749 showed in vivo protective effects against arachidonic acid-induced ear edema and DNCB-induced atopic dermatitis-like symptoms in NC/Nga mice. Conclusion: Our results show that KR-33749, a new 5-LO inhibitor exhibits potent antiinflammatory activities in vitro as well as in vivo. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]