posted on 2016-02-05, 15:55authored byEmmanuel H. Demont, James M. Bailey, Rino A. Bit, Jack A. Brown, Colin
A. Campbell, Nigel Deeks, Simon
J. Dowell, Colin Eldred, Pam Gaskin, James R. J. Gray, Andrea Haynes, David J. Hirst, Duncan
S. Holmes, Umesh Kumar, Mary A. Morse, Greg J. Osborne, Jessica F. Renaux, Gail
A. L. Seal, Chris A. Smethurst, Simon Taylor, Robert Watson, Robert Willis, Jason Witherington
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 S1P1 receptor, but its lack
of selectivity against the S1P3 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 S1P3-sparing S1P1 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.