Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist

A description of the discovery process of CS-2100, a potent, orally active, S1P3-sparing S1P1 agonist has been provided. Its 4-ethyl thiophene structure contributes S1P3-sparing property significantly, which is in accordance with the result of our docking studies with homology models. S1P3-sparing S1P1 agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC50 value of 4.0nM for human S1P1 and over 5000-fold selectivity against S1P3. The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID50 value was determined at 0.407mg/kg. The docking studies of CS-2100 with the homology model of S1P1 and S1P3 showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P3, not in the case of Leu276 in S1P1. This observation gives an explanation for the excellent S1P3-sparing characteristic of CS-2100.