biostudies-literatureFritzemeier RNational Institute of Allergy and Infectious DiseasesNIAID NIH HHS7656-7681https://www.ebi.ac.uk/biostudies/studies/S-EPMC9733493biostudies-literatureUnknown65(11)Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with five G-protein-coupled receptors (S1P1-5) to regulate cellular signaling pathways. S1P export is facilitated by Mfsd2b and spinster homologue 2 (Spns2). While mouse genetic studies suggest that Spns2 functions to maintain lymph S1P, Spns2 inhibitors are necessary to understand its biology and to learn whether Spns2 is a viable drug target. Herein, we report a structure-activity relationship study that identified the first Spns2 inhibitor <b>16d</b> (SLF1081851). In vitro studies in HeLa cells demonstrated that <b>16d</b> inhibited S1P release with an IC₅₀ of 1.93 μM. Administration of <b>16d</b> to mice and rats drove significant decreases in circulating lymphocyte counts and plasma S1P concentJournal of medicinal chemistryDiscovery of In Vivo Active Sphingosine-1-phosphate Transporter (Spns2) Inhibitors.PMC9733493R01 AI144026Fritzemeier RKharel YLynch KRHuang TPeralta APayette MFoster DSantos WLfalseDiscovery of In Vivo Active Sphingosine-1-phosphate Transporter (Spns2) Inhibitors.Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with five G-protein-coupled receptors (S1P1-5) to regulate cellular signaling pathways. S1P export is facilitated by Mfsd2b and spinster homologue 2 (Spns2). While mouse genetic studies suggest that Spns2 functions to maintain lymph S1P, Spns2 inhibitors are necessary to understand its biology and to learn whether Spns2 is a viable drug target. Herein, we report a structure-activity relationship study that identified the first Spns2 inhibitor <b>16d</b> (SLF1081851). In vitro studies in HeLa cells demonstrated that <b>16d</b> inhibited S1P release with an IC₅₀ of 1.93 μM. Administration of <b>16d</b> to mice and rats drove significant decreases in circulating lymphocyte counts and plasma S1P concent2022-01-01T00:00:00Z2022 Jun2025-04-18T23:25:04.356Z2025-04-07T10:59:04.717ZS-EPMC97334933560918910.1021/acs.jmedchem.1c02171