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

[摘要] 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-1phosphate (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 mu M with improved solubility and in vivo potential.

[发布日期] 2021-10-15

[关键词] Sphingosine kinase;Kinase inhibition;Bioorganic synthesis;Microwave synthesis