Identification of potent tricyclic prodrug S1P₁ receptor modulators

Recently, our research group reported the identification of prodrug amino-alcohol 2 as a potent and efficacious S1P₁ receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya 1), whose active phosphate metabolite is an S1P₁ full agonist, in terms of pulmonary and cardiovascular safety. S1P₁ partial agonist 2, however, has a long half-life in rodents and was projected to have a long half-life in humans. The purpose of this communication is to disclose highly potent partial agonists of S1P₁ with shorter half-lives relative to the clinical compound 2. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.