Abstract
The S1P1 receptor is the target of four marketed drugs for the treatment of multiple sclerosis and ulcerative colitis. Targeting an S1P exporter, specifically Spns2, that is "upstream" of S1P receptor engagement is an alternate strategy that might recapitulate the efficacy of S1P receptor modulators without cardiac toxicity. We recently reported the first Spns2 inhibitor SLF1081851 (16d) that has modest potency with in vivo activity. To develop more potent compounds, we initiated a structure-activity relationship study that identified 2-aminobenzoxazole as a viable scaffold. Our studies revealed SLB1122168 (33p), which is a potent inhibitor (IC(50) = 94 ± 6 nM) of Spns2-mediated S1P release. Administration of 33p to mice and rats resulted in a dose-dependent decrease in circulating lymphocytes, a pharmacodynamic indication of Spns2 inhibition. 33p provides a valuable tool compound to explore both the therapeutic potential of targeting Spns2 and the physiologic consequences of selective S1P export inhibition.