title: 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.
abstract: 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.
authors.affiliation: Center for Metabolic Syndrome Therapeutics, Bioorganic Science Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors.forename: Young Sik
authors.initials: YS
authors.lastname: Cho
authors.forename: Chi Hyun
authors.initials: CH
authors.lastname: Kim
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Surh
authors.forename: Nam Sook
authors.initials: NS
authors.lastname: Kang
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
mesh_terms: 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*
chemical_list: 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