Sphingo-guanidines and their use as inhibitors of sphingosine kinase (WO2010078247)

Abstract

The sphingolipid metabolic pathway controls the balance of bioactive lipids including apoptotic ceramide and proliferative sphingosine 1-phosphate and, therefore, represents a potential source of new therapeutic targets for numerous diseases. Targets, such as sphingosine kinases (SphK), have been extensively studied, and numerous strategies have been used to develop inhibitors against these enzymes. The WO2010078247 patent application shows the development of some novel sphingo-guanidines, including their water soluble salts, as inhibitors of SphK, and for use in treating and/or preventing diseases and disorders related to undesirable ceramidase, ceramidase-related or SphK activity, including cancer and other proliferative diseases. The synthesis of two agents D-erythro-2-N-(1′-carboxamidino)sphingosine hydrochloride (LCL146) and L-erythro-2-N-(1′-carboxamidino)sphingosine hydrochloride (LCL351) is described and they have been shown to inhibit SphK activity, be cytotoxic to cancer cells and decrease the migration rate of human prostate (DU145) cells.

Keywords::

• cancer
• proliferative diseases
• sphingo-guanidines
• sphingosine kinase
• sphingosine kinase inhibitors

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