title: Development of novel aminothiazole-comprising 5-LO inhibitors.
abstract: BACKGROUND
  Leukotrienes are pivotal lipid mediators in various immune and inflammatory reactions. Herein, 5-LO is a validated target. 2-Aminothiazoles, as a privileged structure, implicate known 5-LO inhibitors like ST-1083 (IC50 [polymorphonuclear leukocytes (PMNL)] = 0.68 μM), yet deep structure-activity relationships (SAR) have not been established.
  
  
  METHODS
  Compounds were synthesized via Hantzsch thiazole synthesis. Inhibitory activities were evaluated using intact PMNL and purified 5-LO together with cytotoxicity measurements in U937 cells.
  
  
  RESULTS
  We introduced novel functionalities at 2-, 3-, 4- and 5-position of the 2-aminothiazole scaffold and conducted bioisosteric replacement to optimize the parent scaffold. SARs of the 2-aminothiazole scaffold were deduced and extended primarily for inhibition of the 5-LO enzyme.
  
  
  CONCLUSIONS
  SAR studies provided at least two optimized leads (ST-1853, ST-1906) with high potency (IC50 [polymorphonuclear leukocytes] = 0.05 μM), specificity and noncytotoxic behavior.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
authors.forename: Simon B
authors.initials: SB
authors.lastname: M Kretschmer
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
authors.forename: Stefano
authors.initials: S
authors.lastname: Woltersdorf
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
authors.forename: Carmen B
authors.initials: CB
authors.lastname: Rödl
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Vogt
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Häfner
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.|Institute of Pharmaceutical & Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Hofmann
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D016859:Lipoxygenase Inhibitors; D013844:Thiazoles; C004483:2-aminothiazole; D001094:Arachidonate 5-Lipoxygenase
keywords: 5-lipoxygenase; antileukotriene; cancer; inflammation; lead development; structure–activity relationship