title: Discovery of (2-fluoro-benzyl)-(2-methyl-2-phenethyl-2H-chromen-6-yl)-amine (KRH-102140) as an orally active 5-lipoxygenase inhibitor with activity in murine inflammation models.
abstract: OBJECTIVE
  We investigated anti-inflammatory properties of a novel 5-lipoxygenase (5-LO) inhibitor, KRH-102140, in vitro and in vivo. 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. ICR (Institute of Cancer Research) mice were used for in vivo assays. Mouse ear edema was induced by topical application of arachidonic acid. An air pouch was induced by subcutaneous injection of sterile air into mice, followed by zymosan treatment. Sprague-Dawley rats were used for pharmacokinetic studies.
  
  
  RESULTS
  KRH-102140 inhibited 5-LO activity with an IC(50) value of 160 ± 23 nmol/l in parallel with LTB(4) inhibition in RBL-1 cells. Oral administration of KRH-102140 (10-100 mg/kg) reduced ear edema, myeloperoxidase activity and LTB(4) production in murine inflammation models. Oral bioavailability as determined in rats was 66%.
  
  
  CONCLUSIONS
  Our results show that KRH-102140, a new 5-LO inhibitor, exhibits potent anti-inflammatory activities in vitro as well as in vivo.
authors.affiliation: Bioorganic Division, Korea Research Institute of Chemical Technology, Daejon, South Korea.
authors.forename: Young Sik
authors.initials: YS
authors.lastname: Cho
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Huh
authors.forename: Chi Hyun
authors.initials: CH
authors.lastname: Kim
authors.forename: Young-Dae
authors.initials: YD
authors.lastname: Gong
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001578:Benzopyrans / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001596:Benzylamines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D055808:Drug Discovery; D004487:Edema / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D006207:Half-Life; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: C558761:(2-fluorobenzyl)-(2-methyl-2-phenyl-2H-chromen-6-yl-amine); D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D001596:Benzylamines; D016859:Lipoxygenase Inhibitors; D011994:Recombinant Proteins; D007975:Leukotriene B4; D009195:Peroxidase; D001094:Arachidonate 5-Lipoxygenase