Structure-activity profiling of indazole-based derivatives as spinster homolog 2 (Spns2)-dependent S1P release inhibitors.

Sphingosine-1-phosphate (S1P) signaling is a bona fide drug target as evidenced by the S1P receptor modulator drug class for treating multiple sclerosis and ulcerative colitis. Despite this clinical success, on-target adverse events have been reported. To circumvent these, we hypothesized that interdicting the S1P transport cascade will have the same physiological benefits without undesired events. This led to the first reported S1P release inhibitor (SRI), SLF1081851, that supported this concept. Subsequent structural improvements led to new generations of SRIs. Herein, we report a structure-activity relationship study of novel indazole compounds inspired by modifications on a previously reported scaffold. Studies revealed compounds 6c (IC50 = 651 ± 3 nM) and 6k (IC50 = 719 ± 50 nM) to be viable SRIs with molecular modeling suggesting that conformational effects are observed and potency can be influenced by these effects. Thus, both 6c and 6k provide valuable insight into the chemical space within Spns2 and help influence the next generation of SRIs.