Discovery of 3-arylpropionic acids as potent agonists of sphingosine-1-phosphate receptor-1 (S1P1) with high selectivity against all other known S1P receptor subtypes

A series of 3-arylpropionic acids were synthesized as S1P1 receptor agonists. Structure–activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P1 binding against S1P2–5. These highly selective S1P1 agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin transplantation model, supporting that S1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models.

Graphical abstractA series of 3-arylpropionic acids were synthesized as potent and orally bioavailable S1P1 receptor agonists that were highly selective against other S1P receptor subtypes. These highly selective S1P1 agonists were able to lower peripheral blood lymphocytes in mice; one of them (i.e., 13m) was found to be efficacious in a rat skin transplantation model.Figure optionsDownload full-size imageDownload as PowerPoint slide