Characterization of the molecular mechanism of 5-lipoxygenase inhibition by 2-aminothiazoles

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• 作者：Simon B.M. Kretschmer^a ; Stefano Woltersdorf^a ; Dominik Vogt^a ; Felix F. Lillich^a ; Michael Rü ; hl^a ; Michael Karas^a ; Isabelle V. Maucher^a ; Jessica Roos^a ; Ann-Kathrin H&auml ; fner^a ; Astrid Kaiser^a ; Mario Wurglics^a ; Manfred Schubert-Zsilavecz^a ; Carlo Angioni^b ; Gerd Geisslinger^b ; Holger Stark^c ; Dieter Steinhilber^a ; Bettina Hofmann^a ; ^{hofmann@pharmchem.uni-frankfurt.de}
• 关键词：5-Lipoxygenase ; Aminothiazole ; Leukotrienes ; Inflammation ; ST-1853 ; ST-1906
• 刊名：Biochemical Pharmacology
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：123
• 期：Complete
• 页码：52-62
• 全文大小：1778 K
• 卷排序：123

文摘

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.