FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing–remitting multiple sclerosis. It is a potent agonist of the S1P<sub>1sub> receptor, but its lack of selectivity against the S1P<sub>3sub> receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P<sub>3sub>-sparing S1P<sub>1sub> agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines.