Identification of potent tricyclic prodrug S1P<sub>1</sub> receptor modulators.
Marcoux D, Xiao HY, Murali Dhar TG, Xie J, Lehman-McKeeman LD, Wu DR, Dabros M, Yang X, Taylor TL, Zhou XD, Heimrich EM, Thomas R, McIntyre KW, Shi H, Levesque PC, Sun H, Yang Z, Marino AM, Cornelius G, D'Arienzo CJ, Gupta A, Pragalathan B, Rampulla R, Mathur A, Shen DR, Cvijic ME, Salter-Cid L, Lombardo LJ, Carter PH, Dyckman AJ.
Recently, our research group reported the identification of prodrug amino-alcohol <b>2</b> as a potent and efficacious S1P<sub>1</sub> receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya <b>1</b>), whose active phosphate metabolite is an S1P<sub>1</sub> full agonist, in terms of pulmonary and cardiovascular safety. S1P<sub>1</sub> partial agonist <b>2</b>, 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 S1P<sub>1</sub> with shorter half-lives relative to the clinical compound <b>2</b>. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.