Increased expression of sphingosine kinases (SphK) and elevated levels of sphingosine-1-phosphate (S1P) have been implicated in a variety of diseases including: fibrosis, multiple sclerosis, Alzheimer’s, asthma, inflammation, and sickle cell disease. Of the two isoforms, SphK1 is localized in the cytosol, while SphK2 is nuclear bound; however, studies have shown that SphK2 can be exported to the cytosol. SphK1 has been shown to promote cellular proliferation, whereas SphK2 has been shown to be proliferative and pro-apoptotic, depending upon its localization in the cell. As a result of its undefined cellular role, SphK2 has attracted attention as a potential therapeutic target. Previously our group published a Sphk2 selective inhibitor, SLR080811, which displays five-fold selectivity for mSphK2 over hSphK1 and a Ki of 1.3 µM. Modifications to the tail region of this novel scaffold demonstrated that the aryl ring adjacent to the 1,2,4-oxadiazole ring is vital for compound potency and selectivity. Herein, we report the design, synthesis and biological evaluation of our investigation into SLR080811 derivatives containing bicyclic aromatic rings adjacent to the 1,2,4-oxadiazole. These compounds display excellent inhibition activity, good SphK2 selectivity, and low micro-molar range Ki values for hSphK2. Various analogs of our lead compound, SLR080811, were synthesized containing a bicyclic aromatic ring in the tail region. These compounds reveal a preliminary structure-activity-relationship around the bicyclic aromatic tail motif that examines both the substitution around the bicyclic system and optimization of the remaining portion of the tail group.

Investigating aromaticity effects In the tail region of sphingosine kinase 2 selective guanidine-based inhibitors

249th National Meeting (2015)

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