Discovery of Tetrahydropyrazolopyridine
as Sphingosine
1‑Phosphate Receptor 3 (S1P<sub>3</sub>)‑Sparing S1P<sub>1</sub> 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<sub>1</sub> receptor, but its lack
of selectivity against the S1P<sub>3</sub> 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>3</sub>-sparing S1P<sub>1</sub> 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
