Characterization of the molecular mechanism of 5-lipoxygenase inhibition by 2-aminothiazoles.
5-Lipoxygenase (5-LO, EC1.13.11.34) has been implicated in the pathogenesis of inflammatory and immune diseases. Recently, aminothiazole comprising inhibitors have been discovered for this valuable target. Yet, the molecular mode of action of this class of substances is only poorly understood. Here, we present the detailed molecular mechanism of action of the compound class and the in vitro pharmacological profile of two lead compounds ST-1853 and ST-1906. Mechanistic studies with recombinant proteins as well as intact cell assays enabled us to define this class as a novel type of 5-LO inhibitors with unique characteristics. The parent compounds herein presented a certain reactivity concerning oxidation and thiol binding: Unsubstituted aminophenols bound covalently to C159 and C418 of human 5-LO. Yet, dimethyl substitution of the aminophenol prevented this reactivity and slowed down phase II metabolism. Both ST-1853 and ST-1906 confirmed their lead likeness by retaining their high potency in physiologically relevant 5-LO activity assays, high metabolic stability, high specificity and non-cytotoxicity.
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Simon B M
SB
Kretschmer
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Stefano
S
Woltersdorf
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Dominik
D
Vogt
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Felix F
FF
Lillich
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Michael
M
Rühl
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Michael
M
Karas
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Isabelle V
IV
Maucher
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Jessica
J
Roos
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Ann-Kathrin
AK
Häfner
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Astrid
A
Kaiser
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Mario
M
Wurglics
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Manfred
M
Schubert-Zsilavecz
Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, Goethe-University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main, Germany.
Carlo
C
Angioni
Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, Goethe-University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main, Germany.
Gerd
G
Geisslinger
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
Holger
H
Stark
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
Dieter
D
Steinhilber
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany. Electronic address: hofmann@pharmchem.uni-frankfurt.de.
Bettina
B
Hofmann
D002478:Cells, Cultured; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
D016859:Lipoxygenase Inhibitors; D013844:Thiazoles; C004483:2-aminothiazole
5-Lipoxygenase; Aminothiazole; Inflammation; Leukotrienes; ST-1853; ST-1906