Discovery of tetrahydro-pyrazolo-pyridine as sphingosine 1-phosphate receptor 3 (S1P3)-sparing S1P1 agonists active at low oral doses.

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(1) receptor, but its lack of selectivity against the S1P(3) 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(3)-sparing S1P(1) 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.