Design, synthesis and analysis of novel sphingosine kinase-1 inhibitors to improve oral bioavailability.

ID: ALA4808240

Journal: Bioorg Med Chem Lett

Title: Design, synthesis and analysis of novel sphingosine kinase-1 inhibitors to improve oral bioavailability.

Authors: Butler KJ, Castro AA, Dwyer TS, Hardwick LM, Iacino MC, Manore SG, Mays KM, McGlade CA, Hair LN, Parker EW, Smith MR, Turnow MT, Wilson MR, Woodson SR, Cotham WE, Walla MD, Hurlbert JC, Christian Grattan T.

Abstract: The sphingomyelin pathway is important in cell regulation and determining cellular fate. Inhibition of sphingosine kinase isoform 1 (SK1) within this pathway, leads to a buildup of sphingosine and ceramide, two molecules directly linked to cell apoptosis, while decreasing the intracellular concentration of sphingosine-1-phosphate (S1P), a molecule linked to cellular proliferation. Recently, an inhibitor capable of inhibiting SK1 in vitro was identified, but also shown to be ineffective in vivo. A set of compounds designed to assess the impact of synthetic modifications to the hydroxynaphthalene ring region of the template inhibitor with SK1 to obtain a compound with increased efficacy in vivo. Of these fifteen compounds, 4A was shown to have an IC₅₀ = 6.55 μM with improved solubility and in vivo potential.

CiteXplore: 34418572

DOI: 10.1016/j.bmcl.2021.128329

Patent ID: ┄