- SELECTIVE INHIBITORS AND ALLOSTERIC ACTIVATORS OF SPHINGOSINE KINASE
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Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases, such as cancer and vascular remodeling in pulmonary arterial hypertension. Inhibitors of sphingosine kinase 1 and 2 (SK1 and SK2), which catalyze the synthesis of S1P, may be useful anti- proliferative agents. We have synthesized a series of sphingosine-based inhibitors of SK and SK2. Also provided in this invention are compounds that activate SK1 which can be used in diseases such as fibrosis, where intracellular S1P is anti-fibrotic.
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Page/Page column 83-84
(2014/08/19)
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- Structure-Activity relationships and molecular modeling of sphingosine kinase inhibitors
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The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure-activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention.
- Baek, Dong Jae,MacRitchie, Neil,Anthony, Nahoum G.,MacKay, Simon P.,Pyne, Susan,Pyne, Nigel J.,Bittman, Robert
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p. 9310 - 9327
(2014/01/06)
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- Synthesis of aminopyridines via an unprecedented nucleophilic aromatic substitution of cyanopyridines
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The direct reaction of 2- and 4-cyanopyridines with lithium amides affords good yields of the corresponding aminopyridines via displacement of cyanide. Addition of CsF accelerates the reaction and can lead to significantly higher yields.
- Penney, Jonathan M.
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p. 2667 - 2669
(2007/10/03)
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