title: Development and evaluation of ST-1829 based on 5-benzylidene-2-phenylthiazolones as promising agent for anti-leukotriene therapy.
abstract: Different inflammatory diseases and allergic reactions are mediated by leukotrienes, which arise from the oxygenation of arachidonic acid catalyzed by 5-lipoxygenase (5-LO). One promising approach for an effective anti-leukotriene therapy is the inhibition of this key enzyme. This study presents the synthesis and development of a potent and direct 5-LO inhibitor based on the well characterized 5-benzylidene-2-phenylthiazolone C06, whose further pharmacological investigation was precluded due to its low solubility. Through optimization of C06, evaluation of structure-activity relationships including profound assessment of the thiazolone core and consideration of the solubility, the 5-benzyl-2-phenyl-4-hydroxythiazoles represented by 46 (ST-1829, 5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol) were developed. Compound 46 showed an improved 5-LO inhibitory activity in cell-based (IC50 values 0.14 μM) and cell-free assays (IC50 values 0.03 μM) as well as a prominent enhanced solubility. Furthermore, it kept its promising inhibitory potency in the presence of blood serum, excluding excessive binding to serum proteins. These facts combined with the non-cytotoxic profile mark a major step towards an effective anti-inflammatory therapy.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Andreas P
authors.initials: AP
authors.lastname: Lill
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Carmen B
authors.initials: CB
authors.lastname: Rödl
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany. Electronic address: stark@hhu.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany. Electronic address: hofmann@pharmchem.uni-frankfurt.de.
authors.forename: Bettina
authors.initials: B
authors.lastname: Hofmann
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020024:Leukotriene Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000600797:5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol; C000600798:5-(4-methoxybenzylidene)-2-p-tolylthiazol-4(5H)-one; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D013844:Thiazoles; D001094:Arachidonate 5-Lipoxygenase
keywords: 5-Lipoxygenase; Anti-leukotriene therapy; Hydroxythiazoles; Inflammation; Solubility; Structure–activity relationship