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

Pharmacology. 2010;86(2):65-72. doi: 10.1159/000315488. Epub 2010 Jul 17.

Abstract

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 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.

Conclusion: Our results show that KR-33749, a new 5-LO inhibitor exhibits potent antiinflammatory activities in vitro as well as in vivo.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Arachidonate 5-Lipoxygenase / genetics
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Arachidonic Acid / toxicity
  • Cell Line, Tumor
  • Dermatitis, Atopic / drug therapy
  • Dermatitis, Atopic / immunology
  • Dermatitis, Atopic / pathology
  • Dinitrochlorobenzene / toxicity
  • Dose-Response Relationship, Drug
  • Edema / prevention & control
  • Isoenzymes / antagonists & inhibitors
  • Leukotriene B4 / metabolism
  • Lipoxygenase Inhibitors / administration & dosage
  • Lipoxygenase Inhibitors / pharmacology*
  • Lipoxygenase Inhibitors / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Osmolar Concentration
  • Rats
  • Recombinant Proteins / antagonists & inhibitors
  • Skin / drug effects
  • Skin / pathology
  • Skin Diseases / drug therapy
  • Thiazoles / administration & dosage
  • Thiazoles / pharmacology*
  • Thiazoles / therapeutic use*
  • Time Factors
  • Xylenes / administration & dosage
  • Xylenes / pharmacology*
  • Xylenes / therapeutic use*

Substances

  • 4-(4-(4-fluorophenyl)thiazol-2-ylamino)-2,6-dimethylphenol
  • Anti-Inflammatory Agents, Non-Steroidal
  • Dinitrochlorobenzene
  • Isoenzymes
  • Lipoxygenase Inhibitors
  • Recombinant Proteins
  • Thiazoles
  • Xylenes
  • Leukotriene B4
  • Arachidonic Acid
  • Arachidonate 5-Lipoxygenase