title: Structure-activity relationship and in vitro pharmacological evaluation of imidazo[1,2-a]pyridine-based inhibitors of 5-LO.
abstract: BACKGROUND
  5-LO is an important enzyme involved in the biosynthesis of leukotrienes, which are lipid mediators of immune and inflammation responses, with important roles in respiratory disease, cardiovascular disease, immune responses and certain types of cancer. Therefore, this enzyme has been investigated as a potential target for the treatment of these pathophysiological conditions.
  
  
  RESULTS
  5-LO inhibitory potential was investigated in intact polymorphonuclear leukocytes, a cell-free assay, in human whole blood and rodent cells to both elucidate structure-activity relationships and in vitro pharmacological evaluation. Chemical modifications for lead optimization via straight forward synthesis was used to combine small polar groups, which led to a suitable candidate (IC50 [polymorphonuclear leukocytes] = 1.15 µM, IC50 [S100] = 0.29 µM) with desired in vitro biopharmaceutical profiles in terms of solubility (451.9 µg/ml) and intrinsic clearance without demonstrating any cytotoxicity.
  
  
  CONCLUSIONS
  Compound 9l is a novel, potent and selective 5-LO inhibitor with favorable preclinical drug-like properties.
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/LiFF/OSF Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Estel la
authors.initials: El
authors.lastname: Buscató
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wisniewska
authors.forename: Carmen B
authors.initials: CB
authors.lastname: Rödl
authors.forename: Astrid
authors.initials: A
authors.lastname: Brüggerhoff
authors.forename: Astrid
authors.initials: A
authors.lastname: Kaiser
authors.forename: Florian
authors.initials: F
authors.lastname: Rörsch
authors.forename: Edmund
authors.initials: E
authors.lastname: Kostewicz
authors.forename: Mario
authors.initials: M
authors.lastname: Wurglics
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Bettina
authors.initials: B
authors.lastname: Hofmann
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D004252:DNA Mutational Analysis; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000633:toxicity; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D012475:Salmonella / Q000187:drug effects / Q000235:genetics; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: C584218:4-(5-chloro-3-(cyclohexylamino)imidazo(1,2-a)pyridin-2-yl)-2-methoxyphenol; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D011725:Pyridines; D001094:Arachidonate 5-Lipoxygenase; C001439:imidazo(1,2-a)pyridine