抄録
The sphingosine-1-phosphate (S1P) receptor subtype 1 (S1P1) has emerged as a novel therapeutic target for the treatment of multiple sclerosis. FTY720 (fingolimod) is the first functional antagonist of S1P1 that is approved for oral treatment of relapsing-remitting multiple sclerosis. Previously, we have developed novel oxazolo-oxazole derivatives of FTY720 which lack prodrug properties, but acted similar to FTY720 in reducing disease symptoms in a mouse model of experimental autoimmune encephalomyelitis (EAE).
In this study, we have synthesized a novel oxazolo-oxazole compound, denoted ST-1505, that is unrelated to FTY720, and its ring-opened analogue, and characterised their S1P receptor selectivity profiles and their cellular and in vivo functions. Both compounds proved to be active in intact cells but exerted a differential S1P receptor activation profile. Functionally, they acted similar on human endothelial cells and reduced TNFalpha-induced endothelial cell permeability. Finally, in an in vivo mouse model of EAE, both substances reduced clinical signs of the disease when given either prophylactically, or therapeutically when the disease was already manifested. In parallel to the reduced clinical signs, the number of blood T-lymphocytes was also reduced.
Altogether, these data demonstrate that the novel xazolo-oxazole compound ST-1505 and its ring-opened analog act as S1P receptor modulators, and both exert a protective effect on mouse EAE signs suggesting further validation for multiple sclerosis and other autoimmune diseases.
