Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors

Baek, Dong Jae and MacRitchie, Neil and Anthony, Nahoum G and Mackay, Simon P and Pyne, Susan and Pyne, Nigel J and Bittman, Robert (2013) Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors. Journal of Medicinal Chemistry, 56 (22). pp. 9310-9327. ISSN 0022-2623

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    Abstract

    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.