title: Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors.
abstract: Sphingosine kinases (SphK1, SphK2) are main regulators of sphingosine-1-phosphate (S1P), which is a pleiotropic lipid mediator involved in numerous physiological and pathophysiological functions. SphKs are targets for novel anti-cancer and anti-inflammatory agents that can promote cell apoptosis and modulate autoimmune diseases. Herein, we describe the design, synthesis and evaluation of an aminothiazole class of SphK inhibitors. Potent inhibitors have been discovered through a series of modifications using the known SKI-II scaffold to define structure-activity relationships. We identified N-(4-methylthiazol-2-yl)-(2,4'-bithiazol)-2'-amine (24, ST-1803; IC50 values: 7.3 μM (SphK1), 6.5 μM (SphK2)) as a promising candidate for further in vivo investigations and structural development.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Vogt
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Weber
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Ihlefeld
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Brüggerhoff
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.affiliation: Institute of Medicinal and Pharmaceutical Chemistry, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany. Electronic address: stark@hhu.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C466999:SPHKAP protein, human; D013844:Thiazoles; C004483:2-aminothiazole; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C489044:TRIB2 protein, human
keywords: Enzyme inhibitor; ST-1803; Sphingolipids; Sphingosine; Sphingosine-1-phosphate