biostudies-literatureButler KJNIGMS NIH HHS128329https://www.ebi.ac.uk/biostudies/studies/S-EPMC8484043biostudies-literatureUnknown50The 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 solubBioorganic & medicinal chemistry lettersDesign, synthesis and analysis of novel sphingosine kinase-1 inhibitors to improve oral bioavailability.PMC8484043P20 GM103499Hair LNWoodson SRWilson MRButler KJSmith MRWalla MDParker EWTurnow MTMcGlade CAChristian Grattan TCastro AAHardwick LMMays KMIacino MCCotham WEHurlbert JCDwyer TSManore SGfalseDesign, synthesis and analysis of novel sphingosine kinase-1 inhibitors to improve oral bioavailability.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 solub2021-01-01T00:00:00Z2021 Oct2026-05-31T16:08:07.47Z2025-02-19T01:28:28.975ZS-EPMC84840433441857210.1016/j.bmcl.2021.128329