2. Academic Validation
  3. Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors

Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors

  • Bioorg Med Chem. 2014 Oct 1;22(19):5354-67. doi: 10.1016/j.bmc.2014.07.044.
Dominik Vogt 1,  Julia Weber 1,  Katja Ihlefeld 1,  Astrid Brüggerhoff 1,  Ewgenij Proschak 1,  Holger Stark 2
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
  • 2 Institute of Medicinal and Pharmaceutical Chemistry, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany. Electronic address: stark@hhu.de.
PMID: 25150091 DOI: 10.1016/j.bmc.2014.07.044
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.

Keywords

Enzyme inhibitor; ST-1803; Sphingolipids; Sphingosine; Sphingosine-1-phosphate.

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