Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family. The EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (Gα) subunits and beta-gamma (G62 γ) dimers. Ultimately, this S1P-driven signaling results in cell survival, increased cell migration and, often, mitogenesis. The recent development of agonists targeting S1P receptors has provided insight regarding the role of this signaling system in physiologic homeostasis. For example, the immuno-modulator, FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane 1,3-diol), that following phosphorylation, is an agonist at 4 of 5 S1P receptors, revealed that enhancing S1P tone influences lymphocyte trafficking. Further, S1P type 1 receptor (S1P1) antagonists cause leakage of the lung capillary endothelium, which suggests that S1P may be involved in maintaining the integrity of the endothelial barrier in some tissue beds.
Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family and has been demonstrated to induce many cellular processes, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor-cell invasion, endothelial cell chemotaxis and angiogenesis. For these reasons, S1P receptors and sphingosine kinases are good targets for therapeutic applications such as wound healing and tumor growth inhibition.
S1P receptors make good drug targets because individual receptors are both tissue and response specific. Tissue specificity of the S1P receptors is desirable because development of an agonist or antagonist selective for one receptor localizes the cellular response to tissues containing that receptor, limiting unwanted side effects. Response specificity of the S1P receptors is also of importance because it allows for the development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other responses. For example, the response specificity of the S1P receptors could allow for an S1P mimetic that initiates platelet aggregation without affecting cell morphology.
The importance of sphingosine kinase 1 and 2 (SphK1 & SphK2) in cell growth and proliferation has also been recognized. SphK1 & 2 catalyze the phosphorylation of the endogenous lipid D-erythro sphingosine to sphingosine 1-phosphate (S1P). SphK1 & 2 are also responsible for the equilibrium between the anti-apoptotic S1P and its pro-apoptotic metabolic precursor ceramide. Thus, SphK1 & 2 have been proposed to be important drug targets. However, only a small number of compounds have been shown to inhibit the sphingosine kinases, including DL-threo-dihydrosphingosine, N,N-dimethylsphingosine and short-chain DL-erythro-sphingosine analogues. However, these compounds are not suitable as in vivo inhibitors and cannot address questions concerning SphK mediated disease states.
Traditional methods of inhibiting sphingosine kinase have centered on targeting the ATP binding site of the kinase, a strategy that has enjoyed moderate success. However, such methods suffer from limited of selectivity across a wide array of kinases. Additionally, the sequence of the ATP binding domain of SphK1 & 2 is highly conserved across a number of diacylglycerol (DAG) kinase family members, rendering the traditional strategy problematic.
Currently, there is a need for novel, potent, and selective agents that inhibit the substrate-binding domain of the sphingosine kinases (e.g., mouse and human SphK1 and SphK2) that have enhanced potency, selectivity, and oral bioavailability. In addition, there is a need in the art for identification of, as well as the synthesis and use of such compounds. The present invention satisfies these needs.
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