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

Dominik Vogt; Julia Weber; Katja Ihlefeld; Astrid Brüggerhoff; Ewgenij Proschak; Holger Stark

doi:10.1016/j.bmc.2014.07.044

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. Epub 2014 Aug 6.

Authors

Dominik Vogt¹, Julia Weber¹, Katja Ihlefeld¹, Astrid Brüggerhoff¹, Ewgenij Proschak¹, Holger Stark²

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: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
Adaptor Proteins, Signal Transducing / metabolism
Calcium-Calmodulin-Dependent Protein Kinases
Dose-Response Relationship, Drug
Drug Design*
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism
Molecular Conformation
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Adaptor Proteins, Signal Transducing
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
SPHKAP protein, human
Thiazoles
2-aminothiazole
Calcium-Calmodulin-Dependent Protein Kinases
TRIB2 protein, human