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.
OBJECTIVE
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 B(4) (LTB(4)) 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 IC(50) value of 70.5 +/- 6.0 nmol/l in parallel with LTB(4) 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.


CONCLUSIONS
Our results show that KR-33749, a new 5-LO inhibitor exhibits potent antiinflammatory activities in vitro as well as in vivo.
Cho
Young Sik
YS
Center for Metabolic Syndrome Therapeutics, Bioorganic Science Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
Kim
Chi Hyun
CH
Surh
Ji Hee
JH
Kang
Nam Sook
NS
Yoo
Sung-Eun
SE
Cheon
Hyae Gyeong
HG
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000633:toxicity; D045744:Cell Line, Tumor; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004137:Dinitrochlorobenzene / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000517:prevention & control; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009994:Osmolar Concentration; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012871:Skin Diseases / Q000188:drug therapy; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D013997:Time Factors; D014992:Xylenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*
C554538:4-(4-(4-fluorophenyl)thiazol-2-ylamino)-2,6-dimethylphenol; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004137:Dinitrochlorobenzene; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D011994:Recombinant Proteins; D013844:Thiazoles; D014992:Xylenes; D007975:Leukotriene B4; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase